ArticlePDF Available

The Association of Non Viral Liver Diseases from NAFLD to NASH to HCC with the Pandemic of Obesity, Type 2 Diabetes, or Diabesity & Metabolic Syndrome Etiopathogenetic Correlation along with Uti- lization for Diagnostic & Therapeutic Purposes-A Systematic Review

  • Dr kulvinder kaur centre for human reproduction,Jalandhar,Punjab,India.
  • Rotunda Center For Human Reproduction

Abstract and Figures

ABSTRACT Article history Received: 4 August 2021 Accepted: 15 August 2021 Published Online: 25 August 2021 Earlier we have been reviewing the etiopathogenesis (EP) of obesity, type2 Diabetes mellitus (T2DM), Metabolic Syndrome (MetS), Non Alcoholic Fatty Acid Liver Disease (NAFLD) non alcoholic steatohepapititis (NASH), along with its propagation to Hepatocellular carcinoma (HCC) in addition to their therapies exhaustively. T2DM continues to be a major health issue with reaching epidemic to pandemic proportions. Liver disease includes a spectrum of liver injury varying from isolated steatosis known as Non Alcoholic Fatty Acid Liver Disease (NAFLD) to HCC. Clinically it has been observed that the coexistence of NAFLD as well as T2DM is prevalent. T2DM aids in the biological events that results in escalation of robustness of NAFLD that constitutes the primary etiology of chronic liver diseases. In the past 2 decades the incidence of nonviral NAFLD/ NASH, obtained HCC has been escalating at a fast pace. In view of no appropriate agents for therapy of NAFLD/NASH, a thiazolidenedione group of drug pioglitazone used for T2DM therapy is utilized occasionally. Thus here we conducted a systematic review utilizing search engine pubmed, google scholar; web of science; embase; Cochrane review libraryutilizingtheMeSHterms like T2DM; MetS; NAFLD; NASH; HCC; WAT; BAT; VisceralAT; Obesity; BMI; Adipocytokines; adiponectin; leptin; resistin; visfatin; irisin; Hepatokines; angiopoietin like protein 2; hepatosscin; retinol binding protein 4; treatment like pioglitazone; liraglutide; elafibranor CVC (cerviciroc); obeticholic acid; aramchol; selonosertib; simtuzumab; Oxidative stress(OS); insulin resistance (IR) from 1980’s to 2021 till date. We found a total of 1050 articles out of which we selected 236 articles for this review. No meta-analysis was done. Hence diagnosis avoidance in addition to treatment of the generation as well as propagation of NAFLD/NASH are significant areas needing tackling. Thus here we have summarized the EP of NAFLD/NASH, as well as NAFLD/ NASH, obtained HCC along with the present advantageous therapies under trial. For NAFLD/NASH. Moreover how adipocyte obtained adipokines along with live robtained hepatokines might work as both diagnostic in addition to therapeutic targets from NAFLD to HCC.
Content may be subject to copyright.
10 Distributed under creative commons license 4.0
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Journal of Endocrinology Research
*Corresponding Author:
Kulvinder Kochar Kaur,
Kaur Centre For Human Reproduction, 721, G.T.B. Nagar, Jalandhar, Punjab, 144001, India;
The Association of Non Viral Liver Diseases from NAFLD to NASH
to HCC with the Pandemic of Obesity, Type 2 Diabetes, or Diabesity
& Metabolic Syndrome Etiopathogenetic Correlation along with Uti-
lization for Diagnostic & Therapeutic Purposes-A Systematic Review
Kulvinder Kochar Kaur1* Gautam Allahbadia2 Mandeep Singh3
1. Kaur Centre For Human Reproduction, 721, G.T.B. Nagar, Jalandhar, Punjab, 144001, India
2. Ex-Rotunda-A Centre for Human Reproduction, 672, Kalpak Garden, Bandra(W)-Mumbai, 400040, India
3. Swami Satyanand Hospital, Jalandhar, Punjab, India
Article history
Received: 4 August 2021
Accepted: 15 August 2021
Published Online: 25 August 2021
Earlier we have been reviewing the etiopathogenesis (EP) of obesity, type2
Diabetes mellitus (T2DM), Metabolic Syndrome (MetS), Non Alcoholic
Fatty Acid Liver Disease (NAFLD) non alcoholic steatohepapititis
(NASH), along with its propagation to Hepatocellular carcinoma (HCC)
in addition to their therapies exhaustively. T2DM continues to be a major
health issue with reaching epidemic to pandemic proportions. Liver disease
includes a spectrum of liver injury varying from isolated steatosis known
as Non Alcoholic Fatty Acid Liver Disease (NAFLD) to HCC. Clinically
it has been observed that the coexistence of NAFLD as well as T2DM is
prevalent. T2DM aids in the biological events that results in escalation
of robustness of NAFLD that constitutes the primary etiology of chronic
liver diseases. In the past 2 decades the incidence of nonviral NAFLD/
NASH, obtained HCC has been escalating at a fast pace. In view of no
appropriate agents for therapy of NAFLD/NASH, a thiazolidenedione
group of drug pioglitazone used for T2DM therapy is utilized occasionally.
Thus here we conducted a systematic review utilizing search engine
pubmed, google scholar; web of science; embase; Cochrane review
libraryutilizingtheMeSHterms like T2DM; MetS; NAFLD; NASH; HCC;
WAT; BAT; VisceralAT; Obesity; BMI; Adipocytokines; adiponectin;
leptin; resistin; visfatin; irisin; Hepatokines; angiopoietin like protein
2; hepatosscin; retinol binding protein 4; treatment like pioglitazone;
liraglutide; elafibranor CVC (cerviciroc); obeticholic acid; aramchol;
selonosertib; simtuzumab; Oxidative stress(OS); insulin resistance (IR)
from 1980’s to 2021 till date. We found a total of 1050 articles out of which
we selected 236 articles for this review. No meta-analysis was done. Hence
diagnosis avoidance in addition to treatment of the generation as well as
propagation of NAFLD/NASH are signicant areas needing tackling. Thus
here we have summarized the EP of NAFLD/NASH, as well as NAFLD/
NASH, obtained HCC along with the present advantageous therapies under
trial. For NAFLD/NASH. Moreover how adipocyte obtained adipokines
along with live robtained hepatokines might work as both diagnostic in
addition to therapeutic targets from NAFLD to HCC.
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0 DOI:
1. Introduction
Earlier we have been reviewing the etiopathogenesis
(EP) of obesity, type2 Diabetes mellitus (T2DM), Meta-
bolic Syndrome (MetS), Non Alcoholic Fatty Acid Liver
Disease (NAFLD) non alcoholic steatohepapititis (NASH),
along with its propagation to Hepatocellular carcinoma
(HCC) in addition to their therapies exhaustively [1-24]
[besides many more]. T2DM, altogether with obesity,
NAFLD represents the commonest liver disease, associat-
ed -in about 30% of the general population [25]. The prop-
erties of NAFLD are hepatic triglycerides (TG), collection
in addition to insulin resistance (IR) [26]. This is basically
the hepatic presentation of Metabolic Syndrome (MetS)
along with spans a problem encompassing benign with
hepatic steatosis to NASH [27]. Widely the 2 are clubbed as
Non Alcoholic Fatty Acid Liver (NAFL) as well as NASH
[28]. NAFL represents isolated steatosis, whereas NASH
possesses properties of steatosis, lobular inflammation
(alias infiltration by inflammatory cells), hepatocellular
ballooning in the existence or absence of fibrosis [29].
NASH is the one having maximum aggressiveness of the
NAFLD, possesses capacity of propagation to continuous
brosis, with a direct correlation with the risk of Hepato-
cellular carcinoma (HCC) generation that might be a ma-
jor reason for morbidity as well as mortality stimulated by
liver failure (Figure 1) [25,30]. Prevalence of NASH is about
30% in case of patients with NAFLD [31]. Roughly 20% of
patients with NASH having brosis propagate to cirrhosis
[32]. Liver cirrhosis exists in just 50% of NAFLD-associat-
ed HCC [33]. Incidence of NAFLD-associated HCC with-
out cirrhosis is about 8% of total HCC patients [34], while
total incidence rate of HCC in NAFLD as well as NASH
varies from 2-13% [35].
In the clinical scenario NAFLD is present along with
T2DM, obesity, inuencing synergism action resulting in
greater robust liver failures [36]. Prevalence of NAFLD is
thought to be about 75% in cases with T2DM along with
90% in obese cases, that point to a signicant association
of NAFLD with T2DM along with obesity [37]. NAFLD
participates signicantly in escalated incidence of T2DM
in addition to its complications [28]. Further T2DM exac-
erbates NAFLD as well to a more robust type of NASH,
brosis as well as HCC (Figure 1) [37,38].
HCC, represents a highly aggressive cancers [39]. Earlier
hepatitis C virus was believed to the commonest etiology
of HCC [40], although recently it has been illustrated that
till 50% of new onset HCC cases did not have a viral
etiology [41]. The causation of NAFLD/NASH stimulated
HCC is highly complicated, which is correlated with a lot
of modes like cellular plasticity, inammation, apoptosis,
cell cycle as well as cell demise [42]. Hence therapy of
HCC is tough. Moreover it is essential that concentration
is done for avoidance of NAFLD/NASH propagation by
treating them earlier as well as avoidance of its propaga-
tion towards irreversible chronic liver Diseases like cir-
Figure 1. The progression of NAFLD/NASH to HCC
Legend for Figure 1
Courtesy ref no-30-Type 2 diabetes and obesity aggravate the progression of NAFLD/NASH to HCC. Clinically, type 2 diabetes
coexists with NAFLD, and it aggravates NAFLD to more severe forms of NASH, hepatocirrhosis, and HCC, leading to a
metabolically worse phenotype.
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
rhosis as well as HCC. No FDA approved drugs exist till
Besides have reviewed a lot of therapies for NAFLD,
trials under way for NAFLD/NASH therapy, we had re-
viewed the role of adipocytokines in obesity as well as
T2DM associated heart failure (HF). Here we have tried
to update on EP of NAFLD/NASH, as well as NAFLD/
NASH associated HCC, besides the present beneficial
therapies for NAFLD/NASH under trials. Moreover the
initiation of as well as propagation can get influenced
by adipokines/organokines liberated from Metabolic or-
gans when Metabolic impairment exists like T2DM as
well as obesity [43]. Thus here we have concentrated on
organokines liberated by AT as well as liver. That are key
organs for controlling of lipid metabolism. Newer under-
standing with regards to adipoklines/hepatokines which
might serve as potential diagnostic as well as therapeutic
targets in NAFLD/NASH as well as NAFLD/NASH ob-
tained HCC. These are believed to be biological markers
which can anticipate robustness of NAFLD from NAFLD
to HCC.
Thus here we carried out a systematic review on the
association of various metabolic disturbances in the initi-
ation of various liver disorders ranging from NAFLD to
NASH and further towards HCC.
2. Methods
Thus here we conducted a systematic review utilizing
search engine pubmed, google scholar; web of science;
embase; Cochrane review library utilizing the MeSH
terms like T2DM; MetS; NAFLD; NASH; HCC; WAT;
BAT; VisceralAT; Obesity; BMI; Adipocytokines; adi-
ponectin; leptin; resistin; visfatin; omentin; irisin; Hepa-
tokines; angiopoietin like protein 2; hepatosscin; retinol
binding protein 4; treatment like pioglitazone; liraglutide;
elabranor CVC (cerviciroc); obeticholic acid; aramchol;
selonosertib; simtuzumab; Oxidative stress(OS); insulin
resistance (IR) from 1980’s to 2021 till date.
3. Results
We found a total of 1050 articles out of which we se-
lected 236 articles for this review. No meta-analysis was
4. Discussion
4.1 Etiopathogenesis (EP) of Non Alcoholic Fatty
Acid Liver Disease (NAFLD) as well as Non
Alcoholic Steatohepapititis (NASH)
Disturbed Balance -among fatty acids(FA) Metabolism
NAFLD represents the commonest cause of chronic
liver disease. NAFLD occurs, secondary to escalated
triglycerides (TG), collection in the liver [26]. Hence the
balance among FA input as well as -output is key [44]. Im-
plying that generation of NAFLD takes place if levels of
exogenous FA uptake (by dietary ingestion along with ad-
ipose tissue (AT) lipolysis) as well as endogenous FA gen-
eration (DNL in liver is greater than the liberation of FA
(FA oxidation, lipolysis, as well as FA liberation in very
low density lipoprotein (VLDL) TG) from liver (Figure 2).
The liberation of FA from AT as well as effectiveness
of FA uptake by liver are escalated by about 59% in cases
of NAFLD [45], Liver FA is based on the number as well
as action of specic FA transporter as well as FA carrier
proteins like FA translocase (FAT, CD36), FA transport
polypeptide [FAT]) as well as, fatty acids binding protein
(FABP) [46]. Like hepatic expression of FAT/CD36 is sig-
nicantly escalated in cases with NAFLD, as well as he-
patic expression of FABP4 as well as FABP5 is intricately
correlated with intrahepatic TG collection.
In about 26% of patients, the method of aiding liver FA
pool is hepatic Denovo lipogenesis (DNL) [47]. DNL rep-
resents metabolic event which is implicated in generation
new FA from escalated glucose [48]. It signicantly aids in
hepatic lipid collection in etiopathogenesis of NAFLD [48].
The activation of 2 Transcription factors (of sterol regu-
latory element binding protein 1c (SREBP1c), as well as
carbohydrate responsive element binding protein [ChRE-
BP]), enhanced by insulin as well as glucose reaction to
dietary carbohydrate [49]. They possess synergistic signif-
icant part in coordinated control of hepatic DNL. In rest
15% of patients of NAFLD, FA pool is obtained from diet
TG. That is correlated with chylomicron [45].
The maximum lucrative theory in etiopathogenesis of
NAFLDis “2hit’’ posit [50]. 1st hit is IR, secondary to esca-
lated FA ux, 2ND is inammation, correlated with gut ob-
tained endotoxins, Oxidative stress (OS) as well as mito-
chondrial impair. It is intricately associated with NAFLD-
Endotoxin behavior
NAFLD as well as other insulin resistance (IR) dis-
ease is correlated with activation of innate immune sys-
tem=>chronic inflammation [51]. Recently gut obtained
endotoxin, like lipopolysaccharides (LPS) have been
posited to possess a key part in liver inflammation sec-
ondary as well as propagation to chronic Liver Disease [52].
Normally, Endotoxin can get absorbed from the lumen of
the intestine into theportal venous system in addition to
absorbed endotoxin would get cleared fast by the reticulo
endothelial system, specifically kupffer cells [53]. Never-
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
theless, obesity, type2 Diabetes mellitus (DM) along with
other nutritional parameters can change intestinal per-
meability as far as bacterial excessive growth leading to
amucosal barrier that becomes leaky resulting in bacterial
transportation, that points to the liberation of endotoxin
into the systemic circulation [54]. These invasive pathogen-
ic deleterious by products have an impact on the liver li-
pid collection along with acceleration of proinammatory
in addition to brosis events [53].
The part of LPS from gut microbiota (GM) in the gen-
eration of NAFLD as well as NASH has been highlighted
[54]. Circulating LPS amounts small intestinal permeability,
along with bacterial excessive growth are escalated in
cases of NAFLD, with these factors being correlated with
the robustness of hepatic steatosis [54,56]. Livers getting
blood directly from the portal vein remain the major tar-
gets of LPS, alias endotoxin, with LPS toll like receptor 4
(TLR4) being one of the key pathways for the generation
of NAFLD. In case of mouse models, LPS infusion caus-
es stimulation of hepatic steatosis in addition to hepatic
insulin resistance, along with hepatic weight escalation
[57]. LPS results in acceleration of liver damage in mice
receiving a diet lacking methionine-choline [58]. The LPS
binding protein LBP-CD14 complex results in stimulation
of TLR4, that is necessary cascade needed for inamma-
tory propagation [59]. Once LBP deletion occurs it ame-
liorates inammation modulated liver damage [60]. TLR4
possesses the characteristics of stimulation of nuclear fac-
tor κB (NFκB) in addition to liberation of proinammato-
ry cytokines like interleukin-1β (IL-1β), Tumor necrosis
factor alpha (TNFα) as well as IL-6 [61]. Further it has the
ability of recalling damage associated molecular patterns
(DAMP), which get liberated from damaged cells, as well
as modulates FA-stimulated inflammation [51,62]. In the
form of -Pharmacological treatmentsin NAFLD as well
as NASH which target the microbiome, IMM-24 (an anti-
LPS antibody), solithromycin (next generation macrolide
antibiotic) along with TLR4 antagonist [63].
Oxidative stress
Chronic Oxidative stress (OS) is crucial modes re-
sulting in liver damage in NAFLD. Oxidative stress is a
Figure 2. NAFLD development: An imbalance in FA metabolism
Legend for Figure 2
Courtesy ref no-30-NAFLD development is caused by an imbalance in the intrahepatocellular fatty acid (FA) metabolism. Hepatic
TG accumulation is promoted when the FA input is greater than the FA output in the liver. The greater part of FA taken up by liver
is mainly derived from the lipolysis of subcutaneous adipose tissue TG. Another major source of FA in the liver is derived from de
novo lipogenesis that converts excess glucose into FAs. On the other hand, the consumption of FA is possible through the signaling
pathway involved in lipolysis, β-oxidation, and TG secretion (→: signaling pathways related with TG accumulation by FA, →:
signaling pathways related with the consumption of FA).
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
process occurring generally in NAFLD as well as NASH
secondary to escalated generation of Reactive oxygen
species (ROS) [64]. ROS in addition to lipid per oxida-
tion can reason out maximum histological parameters of
NAFLD as well as NASH [65]. In case of hepatic steatosis
patients, mitochondrial ROS Oxidizes hepatic fat depos-
its along with ROS stimulated Fas ligand expression can
generate apoptosis [65]. Both peroxidation of along with
intra cellular membrane can directly result in apoptosis
stimulation as well as necrosis [65]. The robustness of lipid
peroxidation is associated with the robustness of steatosis
in addition to can reason out the correlation among the ro-
bustness of steatosis in addition to the chances of necrosis
inammation along with brosis in NASH [66]. ROS that
is a critical factor in the etiopathogenesis of NASH, can
result in a self created cycle of lipid peroxidation as well
as further cause ROS generation [67]. Alteration of -mito-
chondrial DNA can result secondary to products generated
by lipid peroxidation as well as result in stimulation of
the transcription factor nuclear factor κB (NFκB), which
causes upregulation of TNFα [68]. Hence it further aids in
dysfunctional mitochondrial respiration in addition to es-
calation of ROS generation [68].
Escalation of mitochondrial β-oxidation of FFA is a
signicant generator of ROS in NAFLD as well as NASH
[69]. Enhancement of FFA ux during early NAFLD stage
cause activation of mitochondrial FA-oxidation (FAO),
which points to an early liver compensation modes for
hampering liver fat collection along with sustenance of
liver lipid homeostasis [26]. In case of NAFLD as well as
NASH mitochondrial FAO is further escalated or mini-
mum conserves in the form of a compensation reaction.
The disturbed balance among mitochondrial FAO as well
as electron transport chain (ETC) would aid in escalation
of ROS generation by escalated leaking of electrons from
the ETC [26,69]. ROS stimulated lipid per oxidation results
in inflammation along with hepatic fibrogenesis via the
stimulation of hepatic stellate cells (HSC’s) [70].
Trusted circulation markers which might point OS in
cases with NAFLD have got documented. Urinary 8-iso
prostaglandin F2α (8-isoPGF2α) is believed to be trusted
pointer of OS in vivo [71], as well as soluble NOX2-ob-
tained peptide (s-NOX2-dp) are further agreed upon as
marker that is correlated with ROS production on stim-
ulation of NOX2, that is a member of NADPH-oxidase
family [72]. Enhancement of urinary amounts of 8-isoP-
GF2α as well as serum soluble NOX2-obtained peptide
are believed to be [73] trusted pointers of oxidative stress
in case of chronic inflammation along with metabolic
disease [73]. Further the utilization of these markers can be
done for OS regarding anticipation of robustness of liver
injury in NAFLD [74]. LPS is a significant constituent of
outer membrane of gram negative bacteria which results
in stimulation of exacerbation of inammation as well as
Oxidative stress [75]. Enhancement of circulating amounts
of NOX2 as well as LPS in NAFLD point to a potential
part gut obtained LPS in systemic NOX2 stimulation [76].
Moreover -s- NOX2-dp -amounts -possess a positive cor-
relation of histological grading with steatosis, inamma-
tion, ballooning, brosis as well as NAFLD activity score
(NAS) [76]. Gut obtained LPS might result in activation of
TLR4, as well as TLR4 – modulated NOXs activation can
lead to generation of ROS by macrophage inltration [77].
This can aid to hepatic steatosis in addition to IR [77].
Nevertheless, the variablility of metabolic alterations
take place in NAFLD are not enough to get reasoned out
by “2 hit” posit. Maximum metabolic conditions like obe-
sity, T2DM, Metabolic Syndrome (MetS), dyslipidemia
work as the risk factors for generation of NAFLD by the
“multiple hits’’ implicating a lot of factors (Figure 3) [78].
These “multiple hits’’ are bioactive molecules liberated
from AT, nutritional factors as well as environmental fac-
tors [78].
4.2 Attractive Treatment in NAFLD as well as
With the recently advocated that pioglitazone, along
with high dosages of Vitamin E, efficaciously result in
amelioration of escalation of histological alterations in
cases of NASH [79]. Conversely metformin has no such
action in NAFLD patients [80], as well as ursodeoxycholic
acid (UDCA), has no inuence on liver histological alter-
ations, inflammation, or fibrosis in patients with NASH
[82]. Following are certain Pharmacological examples un-
der Clinical trials as well as might work out as promising
agent for NASH treatment (Figure 4). In addition, the
metabolic prole along with liver histology correlated ef-
fectiveness of these attractive drugs [19,20,81].
Pioglitazone represents an anti diabetic drug thi-
azolidenediones (TZD) class utilized for T2D treatment
[83]. TZD’S are further referred to as glitazones. Two
TZD’s are presently approved by FDA for montherapy or
combination treatment with metformin as well as sulfo-
nylureas for T2D treatment [84]. TZD’s meant for insulin
sensitization aid in controlling glycemia along with insu-
lin resistance (IR) [84]. The maximum signicant benet of
TZD’s was that hypoglycemia doesn’t result secondary to
its utilization with single treatment, with it not being con-
traindicated in patients presenting with renal disease [85].
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
Figure 3. NAFLD/NASH: “Multiple-hits”
Legend for Figure 3
Courtesy ref no-30-Multiple-hits pathogenesis of NAFLD and NASH. NAFLD begins with hepatic lipid accumulation and insulin
resistance, and progresses to NASH with the concert of various factors such as inammation, endotoxin, organokines (adipokines and
hepatokines), and oxidative stress. (▪: Factors related with multiple-hits).
Figure 4. Pharmacological examples
Legend for Figure 4
Courtesy ref no-30-Current therapeutic targets for pharmacological treatment of NAFLD and NASH. There are no FDA-approved
medications for patients with NAFLD/NASH so far. Currently, various pharmacological therapeutic candidates are being applied
to the clinical trials. The illustration demonstrates the targeted pathway and phenotype for treatment of patients with NAFLD and
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
TZD’s work by controlling metabolic pathway by bind-
ing to the nuclear transcription factor Peroxisome Prolifer-
ator adenineActivated Receptor γ (PPAR γ) in addition to
modulation of the expression of the target genes [86]. The
genes possess a part in controlling glucose metabolism,
storage of FA’s along with adipocytes differentiation [87].
In agreement with this PPAR γ agonist escalated the ex-
pression of glucose transporter 4 (GLUT4alias SLC2A4)
A as well as translocation, hamper TNFα as well as result
in enhancement of insulin sensitivity in case of organs
which are insulin sensitive [88]. Conversely T2D treatment
effects increments of weight as an adverse action, since
PPAR γ Receptor’s are markedly expressed in adipocytes
[89]. Enhancement of fat mass is restricted to the subcu-
taneous adipose depots instead of the visceral area [88,90].
That can be prevented by metformin therapy [91].
Recently it got documented that the PPAR γ agonist
Pioglitazone possesses significant actions on NAFLD/
NASH patients. In case of patients with NASH, it ame-
lioratedliver fat collection along with brosis [92]. In case
of patients with NASH in addition to T2DM, it results in
reduction of hepatic steatosis, inammation as well as se-
rum alanine amino transferase (ALT) as well as aspartate
amino transferase (AST) with better liver function [93]. In
rodent models it decreases hepatic gluconeogenesis along
with results in escalation of insulin sensitivity in the liver
as well as other peripheral tissues [94].
Obeticholic acid (OCA); or INT-747; Farsenoid X
receptor [FXR] agonist
Obeticholic acid (OCA) represents a Farsenoid X re-
ceptor [FXR] agonist, that is a nuclear receptor, with sig-
nicant expression in the liver along with small intestine,
having a significant part in the generation in addition to
enterohepatic circulation of bile acids, besides controlling
hepatic glucose as well as lipid metabolism, inammation
as well as lipoprotein constituents in addition to bile acid
generation [95]. In rodent models OCA has anti-inamma-
tory along with, anti-brotic actions on HSC’s as well as
macrophages [96]. The transcriptional repressor small or
short heterodimer partner (SHP), crossreacts with liver
receptorhomolog1 (LRH1), that represents a positive
controller of CYP7A1 which encodes for the rate limiting
enzyme in the classic bile acids generation pathway as
well as represses its ability for transcription [97]. HSC’s
getting exposed to FXR ligands escalated the expression
of the transcriptional repressor SHP along with reduction
of factors correlated with liver brosis [96]. Belief is that
an FXR SHP controlling axis has a significant part in
controlling liver brosis. OCA stimulation of FXR-action
has 100 times greater potency in contrast to the chenode-
oxycholic acid, that is a natural FXR] agonist [98]. Escala-
tion of insulin sensitivity results with the use of OCA in
addition to, reduction of hepatic inammation markers as
well as brosis in patients with T2D as well as NAFLD
[99].Weight reduction results in patients with NASH, with
this weight reduction having extra advantageous actions
on SerumALT/ASTamounts along with liver histology [100].
In addition to that it results in signicant enhances brosis
in patients with NASH [101]. It represents 1 of the agents
holding maximum promise for NASH therapy, is in phase
3 trials [102].
Elafibranor (GFT-505; Peroxisome Proliferator
Activated Receptor (PPAR)-agonist)
PPAR’s represent transcription factors that get activat-
ed by ligand, belonging to the nuclear hormone receptors
superfamily [103]. Their expression occurs in liver, adipose
tissue (AT), heart, skeletal muscle, as well as kidney, be-
sides controlling -oxidation along with gluconeogen-
esis [102]. Three kinds of nuclear receptor isoforms exist;
PPARα, PPAR δ, as well as PPARγ. PPARα, facilitates β
-oxidation, decreases triglycerides (TG), amounts, besides
escalated density lipoprotein (HDL) cholesterol amounts
[104]. Further it hampers nuclear factor κB (NFκB) stimula-
tion of inammatory genes [104]. PPARα agonists like bric
acids derived compounds like brates is in usage widely
for the treatment of hypertriglyceridemia, while it doesn’t
possess significant actions in NAFLD patients [105]. The
reason for this is the existence of PPARα in a lot of organs
besides liver. Akin to PPARα, PPAR δ causes escalation
of FA oxidation along with decreases macrophages in ad-
dition to Kupffer cells activation, in view of its existence
on macrophages [106]. GW50516 represents a synthetic
PPAR δ particular agonist [107]. GW50516 can be thought
of as attractive proposition in Clinical trials, in view of it
possessing potent efciency, however it possesses safety
issues [108].
Elabranor, alias GFT505 is a double PPARα as well
as δ agonist [109]. It attenuates inflammation, apoptosis,
necroptosis in case of NASH mouse model [110]. It led to
reduction of histological hepatic steatosis, inflammation
in addition to, robustness of brosis in both the NAFLD/
NASH as well as brosis mouse model [ 111]. It has a ten-
dency to result in weight reduction, but not that of liver
in case of diet stimulated NAFLD/NASH rodent models
[112]. In cases of obese subjects it enhances hepatic as well
as peripheral insulin sensitivity [113]. Moreover it hampers
proinammatory (interleukin-1β, TNFα as well as F4/80),
in addition to, profibrotic transforming growth factor
beta TGF-β, tissue inhibitors of matrix metalloprotein-
ase (TIMP2), collagen type1, alpha2 as well as collagen
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
type1, alpha2 markers in obese subjects [114]. No -weight
gain was reported [109,115]. Presently it is getting analysed in
phase 3trials in NASH subjects [102].
Arachidylamido cholanoic acid (Aramchol)
Stearoyl-Co A Desaturase (SCD1) Inhibitor
Aramchol represents the liver targeted, an innovative
synthetic lipid molecule,a conjugate of the bile acid, chol-
ic acid as well as arachidic acid (FABACs). It inuences
liver fat metabolism by causing reduction in FA genera-
tion along with escalation of β -oxidation [117]. Furthermore
it results in stimulation of cholesterol efux by activation
of the ATP – binding cassette transporterA1 (ABCA1) [118].
Additionally, it decreases inflammation as well as fibro-
sis in methionine as well as choline decient (MCD) fed
mice [116]. Moreover it tends to ameliorate steatohepapititis
as well as brosis by causing reduction in SCD1 amounts
by controlling the transsulfuration pathway resulting in
escalated glutathione amounts as well as the glutathione
disulde (GSSH/GDX redox couple for appropriate bal-
ance of redox environment [116].
In a phase 2 trial, of patients with NAFLD, Aramchol
decreased the liver fat amounts along with liver histology
[119]. No significant toxicity was observed as seen in cir-
culating ALT as well as AST amounts, besides alkaline
phosphatase (AP) amounts [119]. In view of it targeting
general properties of NASH (like escalated liver fat
amounts, lipotoxicity as well as OS) in addition to brosis
Aramchol is at present getting generated for NASH treat-
ment along with that of brosis. No signicant alterations
in body weight was observed in NASH patients. Phase 3
clinical trials are ongoing in patients with NASH as well
as broses got started in 2019.
Liraglutide (GLP-1Agonist)
Glucagon like peptide 1 receptor (GLP-1) agonists
have got well proven -in the form of attractive anti Dia-
betic agent in animals as well as - patients with T2DM [120].
GLP-1 represents an incretin hormone liberated from the
L-cells in the distal ileum along with colon [121]. It causes
stimulation of pancreas resulting in insulin generation, in
addition to decreases glucagon generation [122]. Endoge-
nous GLP-1 gets broken down by Dipeptidyl Peptidase-4
(DPP-4) enzyme within few minutes whereas Liraglutide
possesses long half life 13h [123].
Exenatide that is a synthetic Extendin-4 was the 1st
GLP-1R agonist that got FDA approval in 2005 for T2DM
treatment in form of monotherapy or as add on therapy
with metformin as well as or sulfonyl urea, in case control
was not sufcient [124].
Liraglutide, the second GLP-1R agonist that got a li-
cense in 2010 by FDA for T2DM treatment. Further in
2020 it got FDA approval for therapy of obesity patients,
dependent on its weight reduction advantages [125]. It pos-
sesses cardiovascular safety while treatment for weight re-
duction [126]. Anorexia secondary to Liraglutide is associat-
ed with glutamatergic POMC neurons, resulting in weight
reduction [127]. In cases of NAFLD as well as NASH it
causes reduction in liver fat amounts, besides with liver
histology getting rectied along with normalization of en-
zymes (ALT as well as AST amounts) without deterioratri-
on of brosis [128]. In view of rodent studies demonstrating
Liraglutide conferred protection to pancreatic β cells from
apoptosis via AKT modulated survival signaling [129].
It enhanced insulin sensitivity by activation of adenine
monophosphate activated -protein kinase (AMPK) as well
as decreases hepatic steatosis by modulation of lipid trans-
portation, β-oxidation, DNL, as well as autophagy [130].
Selonsertib (ASK1 Inhibitor)
Balooning of hepatocytes, points towards the stim-
ulation of the apoptosis pathway, which represents a
hallmark of NASH along with fibrosis propagation [131].
Selonsertib represents -1ST in class Inhibitor of the apop-
tosis signal regulating kinase 1 (ASK1) [132]. Selonsertib
hampers phosphorylation as well as activation of ASK1
by binding to the catalytic kinase domain of ASK1. It has
been posited recently possessing therapeutic potential for
fibrotic Diseases. In case of murine models, ASK1, that
is a serine/threonine kinase, results in phosphorylation of
p38 mitogen activated protein kinase (MAPK) as well as,
resulting in activation ofc-Jun –N terminal kinase (JNK)
resulting in activation of stress response pathways which
exacerbate hepatic inammation, apoptosis in addition to
brosis [133]. In murine models of NASH, it signicantly
enhances besides hepatic steatosis in addition to brosis
correlated with NASH, enhancement of cholesterol, the
bile acid and lipid metabolism [133]. In phase 2 Clinical
trials of NASH patients as well as stage 2-3 brosis, it has
got demonstrated to avoid inammation, brosis, escalat-
ed apoptosis as well as -propagation to cirrhosis [134]. Con-
versely, phase 3 Clinical trials of NASH patients along
with advanced fibrosis were observed to escalate liver
histology, but had no inuence on brosis regression [135].
Simutuzumab (SIM;G6624)
Simutuzumab (SIM) represents a monoclonal Ab,that
targets lysyl oxidase –like 2 (LOXL2) enzymatic activity
which catalyzes the crosslinlinking of collagen in addition
to elastin, resulting in remodeling of the extra cellular ma-
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
trix (ECM) [136]. SIM binds TO LOXL2 as well as hampers
its enzymatic action [137]. Hence it hampers the generation
of growth factors that includes [connective tissue growth
factor (CTGF]/CCN2) as well as TGFβ1 in addition to
results in reduction of fibrosis [138]. In a mouse model
possessing advanced fibrosis stimulated by NASH, SIM
possesses an extra action in combination with the ASK1
Inhibitor [134]. Nevertheless, in phase 2b clinical trials of
patients presenting with advanced fibrosis secondary to
NASH it did not display any action on enhancement of
brosis or cirrhosis that had been veried by hepatic col-
lagen amounts [139].
C-C chemokine receptor CCR Dual -types -2 as
well as 5 (CCR2/CCR5) antagonist -(cenicriviroc)
Liver inflammation is intricately correlated with
chemokines responsible for controlling migration of hepat-
ocytes as well as immune cells [140]. The C-C chemokine
receptor 2 as well as 5 (CCR2, as well as -CCR5) with
their associated ligands CCL2 as well as CCL3-5) have a
correlation with the pathogenesis of Liver inflammation
as well as brosis in the generation of generation [140,141].
CCR2 in addition to its ligand CCL2 escalated hepatic ste-
atosis, macrophages collection, inammation along with
fibrosis [140]. Hepatic Stellate cells (HSCs) on activation,
aid in brosis, liberate CCL5. CCL5 inuences probrotic
action in hepatocytes through its receptor CCR5 as well as
results in stimulation of lipid collection as well as proin-
ammatory factors [141].
CVC or cenicriviroc represents an innovative CCR2,
as well as CCR5 antagonist which is at present in Clin-
ical generation for the therapy of liver fibrosis patients
presenting with NASH [142]. CVC results in reduction of
markers of inammation like IL-1β, IL-6 as well as inu-
ences antifibrotic actions [142]. Fast track movement was
given by FDA in 2015, being a highly lucrative therapy
for NASH as well as liver brosis. In a phase 2b study of
NASH patients presenting with stage 2-3 fibrosis, CVC
-demonstrated enhancement in liver brosis. In addition to
no deterioration in -NASH [143]. At present a phase 3 clin-
icaltrial is ongoing for the therapy of NASH cases with
liver brosis [144].
4.3 Diagnostic Approaches as well as Therapeutic
Targets in NAFLD as well as - NASH –
It is thought that NAFLD as well as NASH are second-
ary to lots of etiopathogenetic factors [78]. Of these we con-
centrate on adipokines liberated from adipose tissue (AT)
which yield fatty acids (FA) as the main site aiding for
NAFLD generation [45]. Various Adipokines are implicat-
ed in the pathogenesis as well as propagation of NAFLD
[145]. Leptin, resistin, in addition to visfatin have a part
in NAFLD generation as well as propagation of NASH
[145,147]. Conversely adiponectin, irisin as well as ghrelin
have advantageous actions on NAFLD as well as NASH
[148,149]. Pharmacological drugs which impact liver histol-
ogy along with pathophysiology might affect the these
adipocytokines amount. This points that adipocytokines
could prove to be signicant therapeutic targets as well as
biomarkers in NAFLD robustness anticipation (Figure 5).
These adipocytokines might further have a signicant role
in generation of HCC.
Adiponectin is a signicant Adipocytokines possessing
the ability to hamper NAFLD generation. A reduction of
circulating amounts of Adiponectin was found in cases
of NAFLD as well as NASH [150]. They had an inverse
association with the robustness of hepatic steatosis as well
as inammation. Pioglitazone, the antidiabetc which had
a benecial action on liver histology escalated adiponec-
tin amounts, in patients withNASH [93]. Nevertheless,
metformin the commonest used antidiabetc agent did not
have any signicant actions on either the liver histology
but decreased the adiponectin amounts [89,151]. Vitamin E
has a robust antioxidant action that can confer protection
to bodies cells against Oxidative stress [152]. It had been
thought to be an alternate medicine advocated for NAFLD
as well as NASH. It enhances liver histology as well as
displays certain adv actions in case of non Diabetes mel-
litus cases with NASH, as well as apparently it enhances
adiponectin amounts [153]. Nevertheless, it has no efcacy
in NASH cases with T2DM [153]. In case of mouse models,
adiponectin represses hepatic lipid collection by lipid me-
tabolism collection by escalated FA oxidation along with
reduction in DNL [94]. Adiponectin has anti inammation,
anti brotic as well as anti apoptosis action [154]. Adiponec-
tin delivery escalates hepatic steatosis along with inam-
mation [154]. Moreover adiponectin expression has an in-
verse association with tumor size as well as recurrence [155].
Leptin is a hormone possessing appetite repression
actions, that gets liberated from fat cells. It controls food
consumption, body fat in addition to insulin sensitivity
[156]. In animal models it is believed to escalate lipid me-
tabolism in case of non AT’s [157]. Nevertheless, in liver, it
accelerates hepatic IR, that results in liver steatosis. Fur-
ther it escalates -liver brosis [156]. Leptin delivery might
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
escalate proinflammatory along with fibrogenic reaction
in the liver through procollagen 1 along with transforming
growth factor beta (TGF-β1) -TGFβ1 [158]. Nevertheless,
in humans its actions are not certain. Escalated circulating
amounts are present in patients with NASH [159]. Leptin
expression has a positive association with robustness of
steatosis, inammation along with brosis [160]. Leptin ex-
pression has a positive association with cell proliferation
in HCC, as validated by proliferation marker Ki67 [133].
Resistin is a proinammatory adipocyte obtained mod-
ulator of hepatic IR [161]. Further it gets expressed in liver
as well. It is correlated with hepatic lipogenesis as well as
liver brosis [162]. Circulating Resistin amounts are escalat-
ed in patients with NAFLD as well as NASH, with circu-
lating Resistin amounts in NAFLD patients are associated
with the robustness of steatosis, inammation along with
brosis [162]. Escalated Resistin amounts are believed to be
correlated with IR. In subjects with NAFLD Pioglitazone
therapy escalates insulin sensitivity along with reduces
plasma Resistin amounts [163].
Ghrelin represents an anti-inflammatory Adipokine.
It is the endogenous ligand for growth hormone secreta-
gogue receptor possessing a peptide structure having 28
amino acids [164]. In patients with NAFLD lesser Ghrelin
are correlated with IR [165]. Plasma Ghrelin amounts possess
a signicant association with liver function. Nevertheless,
Ghrelin amounts are not influenced by Pioglitazone in
the form of one of insulin sensitizers [43]. At the time of as
well as following NAFLD generation, Ghrelin delivery
escalates lipid metabolism, inammation, Oxidative stress
as well as apoptosis [166]. In mouse models Ghrelin result-
ed in reduction in TG amounts as well as the cytokines
TNF-α, IL-6 as well as ameliorated lipotoxicity via auto-
phagy activation in addition to hampering NFκB [167]. In
toto Ghrelin might work as a biomarker for both diagnosis
and management of non alcoholic fatty liver disease.
Figure 5. NAFLD robustness anticipation
Legend for Figure 5
Courtesy ref no-30-Adipokines as diagnostic markers and therapeutic targets in NAFLD and NASH. Adipokines that are secreted
from adipose tissues are classied into anti-inammatory adipokines and pro-inammatory adipokines. Anti-inammatory adipokines
including adiponectin, irisin, and ghrelin inhibit the development and progression of NAFLD and NASH, whereas pro-inammatory
adipokines including leptin, resistin, and visfatin promote the development and progression of NAFLD and NASH.
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
Irisin is a myokine liberated from skeletal muscles on
shivering in addition to exercise stmn [168,169]. Fibronectin
typeIII domain containing 5 precursors (FNDC5) is the
precursor of Irisin. FNDC5/Irisin facilitate thermogene-
sis in AT via ERK as well as p38pathways [170]. It causes
enhancement of glucosehomeostasis along with IR, be-
sides resulting in weight [171] reduction. In the recent past
FNDC5/Irisin induction was obtained at the time of adi-
pocytes differentiation, as well as can get over liberated
from human visceral (VAT) as well as subcutaneous (SAT)
adipose tissue [172]. It is believed to be a compensatory
action. In agreement with this circulating Irisin amounts
are escalated in NAFLD patients, besides being positively
associated with portal inflammation [173], that is further
thought to be a compensatory action.
Visfatin represents an inammatory adipokine enzyme
(alias nicotinamide phospho ribosyl transferase as well
as pre B cell colony enhancing factor). Visfatin amounts
are escalated in T2DM in addition to insulin resistant
situations [174]. Circulating Visfatin amounts are further es-
calated in NAFLD patients, besides being correlated with
hepatic steatosis as well as brosis [175]. Nevertheless, they
don’t get influenced by insulin sensitizers like pioglita-
zone, rosiglitazone as well as metformin [176].
4.4 NAFLD as well as - NASH --Obtained HCC
Pathogenesis of NAFLD as well as - NASH --
associated -HCC
HCC being the 3rd commonest etiology of cancer asso-
ciated mortality [177]. NAFLD as well as NASH associated
HCC represents the most rapidly escalated indication for
liver transplantation [178]. Cirrhosis exists in about 60% of
cases of NAFLD as well as NASH associated HCC [178].
This points that HCC can get stimulated from NAFLD
as well as NASH without cirrhosis. Hence belief is that
inflammatory parameters will also have a key part in
NAFLD/NASH-obtained HCC.
Gut obtained endotoxin
Already detailed how Gut obtained endotoxins work
in the form of alternative inammatory parameters have a
signicant part in the generation of NAFLD/NASH. The
amounts of LPS, alias endotoxins are further escalated in
portal as well as peripheral venous veins of patients with
HCC [179]. They facilitate signicantly the invasion poten-
tial besides inducing epithelial –mesenchymal transition
(EMT), despite them hampering tumor growth as well
[180]. LPS stimulates JNK in addition to MAPK through
TLR4 in HCC cells while hampering of JNK in addition
to MAPK causes a significant reduction in EMT taking
place [180]. Hence the LPS-TLR4 signaling might be one of
the lucrative pathways in controlling the propagation from
NAFLD-NASH to HCC [181].
Adipokines represent inflammatory parameters asso-
ciated with HCC generation. Expression of adiponectin
in human HCC has an inverse association with the tumor
size [182]. It escalates phosphorylation of c-jun N terminal
kinase (JNK) as well as activation of caspase 3 resulting
in apoptosis in HCC [182]. Hampering of JNK phospho-
rylation avoids anti apoptotic actions of adiponectin [182].
Adiponectin has a chemoshielding, besides hepatoshield-
ing actions through sulfatase2 (SULF2) in HCC [183].
Adiponectin deletion facilitates fibrosis as well as HCC
propagation in a choline deficient NASH mouse model
[184]. Conversely high amounts of circulating adiponectin
makes it feasible to anticipate the subsequent generation
of HCC along with poor HCC survival [185]. Moreover ad-
iponectin hampers the oncogenic action of leptin on cell
proliferation, migration as well as invasion of HCC [155].
Leptin expression is escalated in hepatoma tissues as
well as cell lines [186]. Regulatory T Cells(TRegs), effector
CD 4+T cells, as well as CD 8+T cells result in stimula-
tion of the expression of the Leptin receptor (LEPR) in
the liver following generation of HCC [186]. Macrophages
as well as, dendritic cells, upregulate LEPR expression on
the T Cells. Leptin hampers activation of TRegs as well as
function [186]. Escalated Leptin expression in HCC is cor-
related with the expression of human telomerase reverse
transcriptase (hTERT) [187]. Leptin might possess a key
part in obesity associated tumorigenesis. Adipokines that
include adiponectin along with Leptin are critical actors
in obesity associated conditions as well as might be impli-
cated in the etiopathogenesis of NAFLD as well as HCC.
Diagnostic as well as - -Therapeutic target in NAFLD
as well as - NASH --Obtained HCC-Hepatokines
The liver is an organ which liberates cytokines, known
as hepatokines. Adipose tissue (AT) in NAFLD, having
the properties of hepatic TG collection, has a key part
in facilitation of FFA uptake into the liver via lipolysis
[45]. Hence the part of adipokines from AT, that yields
energy source for the generation of NAFLD, would be
very significant in the liver. Conversely, lipid droplets
collection by itself does not influence inflammation as
well as is believed to be simple steatosis. The propaga-
tion from NAFLD to NASH to HCC needs extra factors
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
like oxidative stress, mitochondrial impairment as well as
endoplasmic reticulum (ER) Stress [63,188]. Another signif-
icant factors facilitating NASH in simple steatosis is free
nonesteried cholesterol as well as its oxidized products
[189]. They are cytotoxic, influencing synergistic actions
with TNF, that is markedly escalated in NASH patients
[189]. Hence hepatokines liberated from liver might have an
impact of potency in the propagation of NAFLD to NASH
to HCC (Figure 6) greater propagation.
α2-HS- glycoprotein (Fetuin A as well as - Fetuin B)
Fetuin A, that is one of the liberated glycoproteins is
believed to be the 1st hepatokine demonstrated to be corre-
lated with metabolic diseases [190]. Fetuin A gets positively
correlated with hepatic steatosis as well as IR1 [191]. Its
amounts are escalated in patients with NAFLD, NASH in
addition to T2DM [192]. In the form of a signicant source
of NAFLD generation, FFA escalates proinflammatory
Fetuin A expression [24]. FFA stimulated Fetuin A works
as an endogenous ligand of TLR4, as well as accelerates
lipid modulated insulin resistance [193]. FFA can further
escalate the recruiting of NFκB to the Fetuin A promoter
as well as escalate the generation as well as liberation of
Fetuin Ain primary hepatocytes [194]. Pioglitazone signi-
cantly represses serum Fetuin A amounts in patients with
T2DM [195]. Pioglitazone hampers mRNA as well as pro-
tein amounts of hepatic Fetuin A along with oral delivery
of pioglitazone in mice partly mitigated IR with reduction
in hepatic Fetuin A expression [196]. These data point that
Fetuin A might serve as a therapeutic target of NAFLD/
NASH as well as IR. Moreover circulating Fetuin A
amounts are escalated in patients with HCC [197]. Fetuin
B -might also work out to be an independent pointer of
NAFLD generation [198]. It also stimulates hepatic steato-
sis, IR, glucose intolerance [166,199]. It results in phospho-
rylation amounts as well as exacerbates LXR/SREBP1c
modulated hepatic lipogenesis [200]. Conversely, circulat-
ing Fetuin A as well as circulating Fetuin B amounts in
NAFLD patients have a negative correlation with liver
brosis [201].
Figure 6. the propagation of NAFLD to NASH to HCC
Legend for Figure 6
Courtesy ref no-30-Hepatokines that are secreted from the liver are closely associated with the progression from NAFLD to NASH
to HCC. Hepatokines including Fetuin-A, Fetuin-B, RBP4, and FGF19 play an important role in NAFLD and NASH. They are
associated with hepatic lipid accumulation, insulin resistance, and inammatory signaling pathways. Additionally, ANGPTL4 and 8
tend to function in opposite ways in HCC tumorigenesis.
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
Retinol Binding protein-4 (RBP4)
The liver has a central part in Vitamin A metabolism.
In NAFLD hepatic Vitamin A homeostasis gets disturbed
[202]. RBP4 is a particular Retinol/Vitamin A carrier protein
liberated from the liver. Further it also gets liberated from
adipocytes along with macrophages [203]. Serum RBP4
amounts are correlated with NAFLD generation [204].
Circulating RBP4 amounts have a positive association
with body mass index (BMI) as well as IR [205]. In case of
moderate to severe NASH, escalated amounts of RBP4
was association with lobular inflammation in addition
to fibrosis scores [206]. In case of cirrhosis, expression of
RBP4 escalated hepatic glucose generation, but not insu-
lin sensitivity [207]. One knows that Vitamin A homeostasis
is impaired in addition to decreased secondary to liver -
brosis as well as cirrhosis. Signicantly escalated amounts
of RBP4 might become a marker for NAFLD generation,
along with the lower amounts of RBP4 might further be a
marker for propagation of NASH with brosis in NAFLD
stages [204].
Hepassocin (HPS)
Hepassocin is a hepatocyte obtained brinogen corre-
lated peptide (HFREP-1), a hepatokine which is implicat-
ed in during liver regeneration [208]. In case of mice along
with human patients with NAFLD, plasma HPS amounts
are escalated [209]. Overexpression of hepassocin escalated
hepatic lipid collection, besides NAFLD activity scores
(NAS), while its removal enhances them [209,210]. Serum
HPS amounts are escalated with the amounts of inflam-
matory cytokines in addition to lipogenic gene expres-
sion [210]. HPS stimulated hepatic steatosis gets triggered
via the extracellular signal regulated kinase (ERK1/2)-
based pathway [210]. FFA stimulates expression of HPS
[211,212]. Oleic acid the maximum distributed unsaturated
fatty acids, stimulates expression of HPS vis the Signal
Transducers and Activators of Transcription3 (STAT3)
signaling [211]. Palmitate, that has the maximum content
of saturated fatty acids, stimulates expression of HPS via
endoplasmic reticulum (ER) stress – modulated p38 acti-
vation by C/EBPβ in primary hepatocytes [212]. In addition
to that hepatic expression of HPS gets escalated by partial
hepatectomy in mice, as well as gets stimulated by hepatic
nuclear factor 1(HNF-1α) via the IL-6/STAT3 pathway
[213]. Delivery of HPS confers protection against liver dam-
age as well as escalates survival in rats with hepatitis [214].
Liver particular expression of HPS gets suppressed with
the downregulation of the correlation of HNF1 alpha with
reduced amounts of hepassocin in human Hepatocellular
carcinoma [213,215].
Fibroblast -growth -factor 19 and -21 (FGF19 as
well as - - FGF21)
FGF19 as well as FGF21 belong to the FGF19 family,
which needs the Klotho proteins as cofactors. They stim-
ulate FGFR4 along with Klotho, that has an abundance of
expression in hepatocytes [216]. FGF19 as well as FGF21
have the role of controlling glucose, lipid as well as bile
acid metabolism [217].
Fibroblast -growth -factor 19 (FGF19)
In case of NASH, the amounts of serum FGF19, Fibro-
blast growth factor receptor 4(FGF R4), along with bile
acids are signicantly escalated, that causes dysfunction
of FXR as well as FGFR4 modulated signaling [218]. In cas-
es of NASH, FAF analogue signicantly causes reduction
in hepatic lipid accumulation. Conversely up regulation
of FGF19 is correlated with the propagation, recurrence,
in addition to worst prognosis of HCC [219]. The β- Klotho
proteins are further escalated in liver as well as serum of
subjects with HCC [220].
Fibroblast -growth -factor 21 (FGF21)
The hepatokine FGF21 possess advantageous actions
on hepatic lipid metabolism. It escalates lipid oxidation,
represses DNL, in addition to escalate insulin resistance
by inhibiting mammalian target of rapamycin complex1
(mTOR) [221]. Hepatic FGF21 expression possesses a
positive association with adipocyte in addition to intra
hepatic TG, with its serum amounts being escalated by
significant amounts in subjects with obesity, NAFLD
as well as T2DM [222]. Serum amounts of FGF21 are es-
calated in obese children with or without NAFLD [223].
Escalated amounts of FGF21 are believed to be based on
the robustness of steatosis, along with positive association
with NAS [224]. Cases of advanced NASH can be labelled
on the basis of properties of circulating FGF21 amounts
in combination with inammatory factors (cytokeratin 18,
M30antigen, IL-1Ra, pigment epithelium-based factor, as
well as osteoprotegrin) [225]. Enhancement of serum as well
as hepatic FGF21 amounts are seen in cirrhosis as well as
HCC [226].
Angiopoietin –Like Protein- 8 (betatrophin/
ANGPTL8/betatrophin represent a circulating hepa-
tokine also called TD26 as well as lipasin [227]. It is sig-
nificantly expressed in liver as well as visceral adipose
tissue (VAT) [228]. Over expression of ANGPTL8 in brown
adipose tissue (BAT) escalates lipoprotein lipase (LPL)
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
action along with TG uptake [168,229] [reviewed by us in
169]. Serum ANGPTL8 are signicantly escalated in pa-
tients with pre Diabetes as well as type2 Diabetes [230]. It
has been documented that ANGPTL8 is not implicated in
Pancreatic βcells expansion, although it has a part in con-
trolling glucose along with lipid metabolism in mice [231,232].
In addition ANGPTL8 expansion is significantly esca-
lated in HCC [228]. It crosstalks with SREBP1, secondary
to which it facilitates lipogenesis along with tumor cell
proliferation in HCC [228]. Hence it is believed that it has a
positive association with the tumor size. ANGPTL8 needs
ANGPTL 3 instead of controlling LPL by itself [229,233].
ANGPTL 3 controls TG metabolism by directly hamper-
ing LPL [229,233]. ANGPTL 4 gets markedly expressed in
liver as well as adipose tissue, in addition to can controls
TG metabolism by hampering LPL action [229,235]. Never-
theless, ANGPTL 4 expression reduction exists in HCC,
besides Over expression of ANGPTL4 hampers hepato-
carcinogenesis along with metastasis of HCC [236].
5. Conclusions
Over the past 2 decades the percentage of HCC cases
possessing non viral etiology has been escalating at a fast
pace. Secondary to this the signicance of NAFLD/NASH
obtained HCC has been showing up. At present what holds
the truth is that management of subjects with NAFLD/
NASH is usually carried out with the utilization of medi-
cines for the treatment of type2 Diabetes mellitus as well
as hyperlipidemia. The adverse actions which show up
following the long term utilization have to be taken into
account. Hence proper therapeutic targets along with FDA
approved treatments are required at war footing. It is be-
lieved that the causation of failure of generation of a ther-
apy for subjects with NAFLD/NASH in spite of contin-
uous attempts are i) pathogenesis is still not totally clear;
ii) absence of actions; iii) safety issues. Adipose tissue as
well as the liver constitute the most signicant organs that
are correlated with lipid metabolism. Hence it is essential
to watch adipokines as well as hepatokines that can work
as diagnostic in addition to therapeutic targets as well as
signaling pathways that get targeted by the present ther-
apies. In addition, to that it needs to get deep insight via
the classication as per the etiology of NAFLD. It would
yield a signicant point of view for the regulation of the
metabolic phenotype from NAFLD to NASH to HCC. At
present it has been accepted that think of NAFLD as being
occurring secondary to a concert of different parameters
that include nutritional factors, Gut Microbiota, genetic
in addition to epigenetic factors as well as adipokines in
addition to hepatokines. To be able to achieve a successful
therapy, it is essential to watch different factors in a wider
[1] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.
Kochar Kaur -K,Allahabadia GN,Singh M(2016).
An update on Aetiopathogenesis and management of
Obesity.Obes Control Ther3(1):1-17. Diabetes Res
Clin Pract 2014;103:137-49.
[2] Kochar Kaur -K,Allahabadia GN,Singh M(2013)
Current management of obesity in an infertile female.
Recent Advances -and Future Prospectives.Drugs J
Pharm Nutr Soc;3:1-13.
[3] Kochar Kaur -K,Allahabadia GN,Singh M .Thera-
peutic Utilization of Neuro Imaging Studies in Obesi-
ty for Optimal Utilization of Drugs used in Treatment
for Obesity-Lessons Learnt from Bariatric Surgery. -J
Ageing Restor Med (JARM)n2019;2(2):89-97.
[4] Kochar Kaur -K,Allahabadia GN,Singh M . Existing
and prospective pathways for intervention in treat-
ment of obesity in a novel way-a review; -MOJ Drug
Des Develop Ther. 2018;2(3):95-105.
DOI: 10.15406/mojddt.2018.02.00035.
[5] Kochar Kaur -K,Allahabadia GN,Singh M .Advances
in BAT physiology for understanding and translating
into Pharmacotherapies for obesity and comorbid-
ities. MOJ Drug Des Develop Ther. 2018;2(5:166-
DOI: 10.15406/mojddt.2018.02.00057.
[6] Kochar Kaur -K,Allahabadia GN,Singh M. Targeting
macrophage polarization for therapy of diabesity–the
feasibility of early improvement of insulin sensitivity
and insulin resistance-a comprehensive systematic
review. J Diab Metab Disorder Control. 2021;8(1):6-
[7] Kochar Kaur -K,Allahabadia GN,Singh M. Are we at
the verge of nding a new efcacious pharmacother-
apy for obesity in the form of agonism at triple drug
receptors: glucagon, Glucagon like peptide1 (GLP1),
glucose dependent insulin tropic peptide (GIP). MOJ
Drug Des Develop Ther. 2019;3(1):22-27.
[8] Kochar Kaur -K,Allahabadia GN,Singh M. Targeting
Orexin Neurons for Treatment of Obesity is It Feasi-
ble in Human Being-A Systematic Review. Journal
of Neurology Research Reviews & Reports. J Neurol
Res Rev Rep, 2019; 1(1): 1-9.
[9] Kochar Kaur -K,Allahabadia GN,Singh M .Impor-
tance of simultaneous treatment of obesity and diabe-
tes mellitus: A sequelae to the understanding of dia-
besity-A review.Obes Res Open J. 2019; 6(1): 1-10.
DOI: 10.17140/OROJ-6-136.
[10] Kochar Kaur -K,Allahabadia GN,Singh M . Role of
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
Adipocyte Impairment in Heart Failure Induction in
Subjects that are Obese along with Prediabetes and
Overt Diabetes Mellitus - A Systematic Review. In-
ternational Journal of Cardiology and Cardiovascular
Disorder2021; 2(1) :1-21.
[11] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. A
Mini Review on Development of Newer Therapies
for Non Alcoholic Fatty Acid Liver Disease with
Emphasis on Vitamin D and its Receptor and Allyl
Isothiocyanate (AITC)”. Acta Scientific Nutritional
Health 2019; 3(12) :1-5.
[12] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. An
Update on Further Progression of NAFLD, NASH
with Prospective Therapies Like L-Carnitine (LC),
Nicotinamide Ribose (NR) Combination, as well as
Apical Sodium Dependent Bile Acids Transporter
(ASBT) or Volixibat and Silybin as Alternatives. Int
J Clin Med Cases. 2020 Jan;3(3):138.
DOI: 10.31021/ijcmc.20203138-29/1/2020 jan 29.
[13] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.
Have Probiotics and Synbiotics passed the test of
time to be implemented in management of obesi-
ty and related metabolic disorders-a comprehen-
sive review. Adv Obes Weight Manag Control.
DOI: 10.15406/aowmc.2019.09.00269.
[14] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.
Will Probiotics Provide the Answer for Therapy of
Non-alcoholic Fatty Liver Disease (NAFLD)? – A
Systematic Review. Biochem Physiol -2020;9: 257.
[15] Kulvinder Kochar Kaur,Allahbadia GN,Singh M..
Rosmarinic Acid-A New Hope for Liver Diseases
Like Cirrhosis, Hepatocellular Carcinoma-Need-
sTranslation to Humans”. EC Endocrinology and
Metabolic Research 2019;4(6 ): 289-301.
[16] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.
How do we apply advances in knowledge of Hepatic
Macrophages in treating Liver Diseases especially
non alcoholic -fatty liver disease( NAFLD), non
alcoholic steatohepapititis( NASH), with the increas-
ing incidence of Diabesity-A Systematic Review.EC
Endocrinology and Metabolic Research published
[17] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.
Mechanisms that associate extension of Nonalcoholic
fatty liver diseases(NAFLD) to NASH (Nonalcoholic
steatohepatitis) and further progressing to cirrhosis
and Hepatocellular carcinoma(HCC) in addition to
few proposed biomarkers for poor prognosis.J Gy-
naecol 2021;1(16):1-18.
[18] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.
How can we optimize therapy of Non Alcoholic
Fatty Acid Liver Disease-A Short Communication
on role of Astragaloside IV and other prospective
agents”. Clinical Research and Clinical Case Reports,
DOI: http;//
[19] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.
Paradoxical Additional Role of SGLT2 Inhibitors
Beyond Glycosuria in Controlling Obesity, NAFLD
Treatment, Pancreatic β Cell Protection Besides
Therapy for Diabetes Mellitus, CVOT and Renopro-
tection-A Minireview”. Acta Scientic Gastrointesti-
nal Disorders 4.7 (2021): 15-26.
[20] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.
’An update on management of Nonalcoholic Fatty
Liver Disease &Nonalcoholic Steatohepapititis-Is
-the time ripe for achieving -resolution of NAFLD
&NASH soon’’.2021Under review.
[21] Khan MAB,Hashim MJ,King JK,Govender RD,Mus-
tafa H,AlKaabi J. -Epidemiology of type2 Diabetes
mellitus- Global burden of disease and forecasted
trends.J Epidemiol Glob Health 2020;10:107-11.
[22] Masmiquel L,Leiter LA,Vidal J,Bain S,Petrie J,-
Franek E,etal.LEADER 5: Prevalenceand cardiomet-
abolic impact ofobesity in cardiovascular high risk
patients with type2 Diabetes mellitus:baseline global
date from the LEADER trial. Cardiovasc Diabetol
[23] Ng ACT,Delgado V,Borlaug BA,Bax JJ.Diabesity
:the combined burden of obesity -and Diabetes on
heart disease and the role of imaging .Nat Rev Cardi-
ol 2021;108:291-304.
[24] Gonzalez-Gross M,Melendez A.Sedentarism,active
lifestyle and sport:impact on health and -obesity pre-
vention.Nutr Hosp2013;5:89-98.
[25] Younossi ZM .Nonalcoholic fatty liver disease a
global public healthperspective. J Hepatol 2019.;70:
[26] Sunny NE,Bril F,Cusi K. Mitochondrial Adaptation
in non alcoholic -fatty liver disease:novel mecha-
nisms and treatmentstrategies. Trends -Endocrinol
Metab 2017; 28:250-60.
[27] Abd-El-Khader SM, El-Den Ashwamy EM. Nonal-
coholic fatty -liver disease:the diagnosis and man-
agement. World JHepatol 2015; 7:846-58.
[28] Arulanadan A,Loomba R.Non invasing testing -for
NASH and NASH with advanced fibrosis:are we
there yet?Curr Hepatol Res 2015;14: 109-18.
[29] Chalasani N, Younossi ZM, Lavine AE,Charlton M,
Cusi K, RinellaM, -etal .The diagnosis and manage-
ment of - non alcoholic fatty liver disease: practice
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
guidance from the -American -Association for the-
study of - Liver disease. -Hepatology -2018;67: 328-
[30] Kim H, Lee DS,An TH,Park HJ,Kim WK,Bae
KH,Oh KJ.Metabolic spectrum of liver failure in
type2 - Diabetes and obesity:From NAFLD to NASH
to HCC.Int J Mol Sci 2021;22:4295.
[31] Mahjoubin-TehranM,DeVentisA.Mikhailidis DP,At-
kin SL,Mantzoros CS,Jamialahmadi T, -etal . Non-
alcoholic fatty liver disease and steatohepatitis:state
of the art on effective therapeutics based on the
gold standard method for diagnosis. Mol Metab
[32] Loomba R.Adams LA.The 20% rule of NASHpro-
gression:the natural history of -advanced brosisand
cirrhosis caused by NASH. Hepatology 2019;70:
[33] Wong SW,Ting YW,Chan WL. Epidemiology of -non
alcoholic fatty liver disease related Hepatocellular
carcinoma and its implications.JGH Open 2018;2:
[34] BenhammouJN,Lin J,Hussain SK, El-Kabany
M.Emerging risk factors for non alcoholic fatty liver
disease - -associated Hepatocellular carcinoma. Hep-
atoma Res -2020;6:35.
[35] Huang DQ,El-SeragHB, Loomba R. Global Epide-
miology of NAFLD- related HCC:Trends ,predic-
tions,riskfactors and prevention. Nat Rev -Gastroen-
terol -Hepatol 2021;18:223-38.
[36] Anstee QM,McPherson S,Day CP.How big a
problem -is Nonalcoholic fatty liver disease?BM-
[37] Tomah S,Alkhoury N,Hamdy O. Nonalcoholic fatty
liver disease and type2 Diabetes:where do Diabetolo-
gists stand? Clin Diabetes Endocrinol 2020;6:9.
[38] Jarvis H,Craig D,Barker R,Spiers G,Stow D, Anstee
QM, -etal .Metabolic risk factors -and incident ad-
vanced liver disease in Nonalcoholic fatty liver dis-
ease(NAFLD) :a systematic review and -meta-analy-
sis of -population -based observational studies.PLoS
Med 2020;17:e1003100.
[39] Miya narsky L,Manchem Y,Shibolet O. Treatment of
Hepatocellular carcinoma:steps forward but but still
a long way to go. World JHepatol 2015; 7:566-74.
[40] Goto K,Roca Suarez AA,Wrench F,Baumert TF,Lup-
berger J.Virus and Hepatocellular carcinoma:when
the host loses its grip. Int J MolSci 2020;21):3057.
[41] Enomoto H,Ueno Y,Hiasa Y,Nishikawa H,Hige S,Ta-
ki kawa Y, -etal .Japan etiology of LiverCirrhosis
Study Group in the 54th annual meeting of JSH.The
transition in the -etiologies of -Hepatocellular car-
cinoma-complicated LiverCirrhosis in anationwide
survey of Japan.J Gastroenterol -2021;56:158-67.
[42] Kinoda T, Goto K,Hirotsu Y,Masuzaki R,Moriyama
M,Omata M. Molecular mechanisms :connections
-between Nonalcoholic fatty liver disease, steatohe-
papititis and Hepatocellular carcinoma. Int J MolSci
[43] Kim WK,Bae KH, Lee SC,Oh KJ.The latest insights
into adipokines in -Diabetes. J Clin Med - - 2019;
[44] David Hojland L,Kykkesfeldt J,Tveden Nyborg .
Molecular mechanisms of hepatic lipid accumulation
in Nonalcoholic fatty liver disease. Cell Mol Life Sci
-2018;75: 3313-327.
[45] Donnelly KL,Smith CI,Schwazenberg SJ,Jessurun
J,Boldt MD,Parks EJ.Sources of fatty acids stored
in liver and secreted via lipoprotein in patients with
- non alcoholic fatty liver disease. J Clin Invest
[46] Michele AB, David EC. Triglyceride metabolismin
the liver .Compr Physiol -2017;8: 1-8.
[47] Draison F,Moulin P,Beylot M.Contribution of -hepat-
ic Denovo lipogenesis and resterification of plasma
non esteried fatty acids to plasma Triglyceride syn-
thesis in Nonalcoholic fatty liver disease. Diabetes
-Metab -2003;29:478-85.
[48] Chiu S,Mulligan K,Schwartz JM.Dietary arbohydrate
and fatty liver disease: Denovo lipogenesis. Curr
-Opin Clin Nutr Metab Care 2018;21:277-82.
[49] Linden AG,LiS,Choi HW,Fang F,Fukasawa U, Ueda
K, -etal .Interplay between ChREBP and SREBP1c
coordinates -postprandial glycolysis and lipogenesis
-in livers of mice.J Lipid Res -2018;59: 475-87.
[50] Day CP,James OF. Steatohepapititis:A tale of two
hits? Gastroenterology 1998;114:842-45.
[51] Arrese M,Cabrera D,Kalergis AM,Feldstein AE. In-
nate immunity and inammation in NAFLD/ NASH.
Dig Dis Sci 2016;61:1294-1303.
[52] Fukut H.Gut- liver axis in liver cirrhosis :how to
manage leaky gut and endotoxaemia. World J Hepa-
tol 2015; 7:425-42.
[53] JuC,Tacke F. Hepatic Macrophages in homeostasis
and -liver diseases:from pathogenesis to novel ther-
apeutic strategies. Cell Mol Immunol 2016;13: 316-
[54] Chakaroun RM,Massier L,Kovacs P.Gut microbiome,
intestinal permeability - and tissue bacteria in met-
abolic disease:perpetrators or bystanders? Nutrients
[55] Carpino G,Del Ben M,Pastori D,Carnevale R,Baratta
F,Overi D, -etal .Increased liver localization of lipo-
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
polysaccharides in human and experimental NAFLD.
Hepatology 2020;72: 470-85.
[56] Harte AL,Da Silva NF,Creely SJ,McGeeKC,Billy-
yard T,Youssef-Elabd EM, -etal .Elevated endotoxin
levels in non alcoholic fatty liver disease.J In-
[57] Cani PD, Amar J, Iglesias MA, Poggi M, Knauf
C, Bastelica D, et al. Metabolic endotoxemia ini-
tiates obesity and insulin resistance. Diabetes.
[58] Kudo H,Takahara T,Yata Y,Kawai K,Zhang W,Sugi-
yama T. Lipopolysaccharides triggered TNFα-in-
duced apoptosis in murine model of non alcoholic
steatohepapititis model.J Hepatol 2009;51:168-75.
[59] Ma J,Zhou Q,Li H. Gut microbiota and Nonalcoholic
fatty liver disease:insights on mechanisms and thera-
py. Nutrients -2017;9:1124.
[60] Jin C,Engstler AJ,Ziegenhardt D,Bishoff SC,Traut-
wein C.Bergheim I.Loss of -lipopolysaccharides
binding protein attenuates -the development of diet
induced - non alcoholic fatty liver disease in mice.J
Gastroenterol Hepatol -2017;32:708-15.
[61] Lawrence T.The nuclear factor κB pathway in
inflammation.Cold Spring HarbaPerspect Biol
[62] Lancaster GI,Langley KG,Berglund NA,Kammoun
HL,Reibe S,EstevezE, et al.Evidence that TLR4 is
not a receptor for saturatedfatty acids but mediates
lipid-induced inammation by reprogramming -mac-
rophagemetabolism. Cell Metab 2018;27:1096-110.
[63] Sumida Y,Yoneda M.Current -and future Pharmaco-
logic therapies for NAFLD/ NASH. J Gastroenterol
[64] Masarone M,RosatoV,DallioM,Gravina AG,Aglitti
A,LoguercioC, et al.Role of Oxidative stress in the
pathogenesis of NAFLD. Oxid Med Cell Longev
[65] Simoes ICM,Fontes A,Pinton P,Zischka H,Wieck-
owskiMR. Mitochondria in non alcoholic fatty liver
disease. Int J Biochem Cell Biol 2018;95:93-99.
[66] Serfaty L,Lemoine M.Denition and natural history
of metabolic steatosis: Clinical aspects of NAFLD,
NASH and cirrhosis. Diabetes -Metab -2008;34:634-
[67] Palmieri B,SblendorioV. Oxidative stress detec-
tion:what for ?Part II.Eur Rev Med Pharmacol
[68] Forrester SJ,Kikuchi DS,Hernandes MS,X-
uQ,Griendling KK. Reactive oxygen species in
Metabolic -and -inflammatorysignaling.Circ Res
[69] Chen Z,Tian R,She Z,Cai J,LiH. Role of Oxidative
stress in the pathogenesis of NAFLD.. Free Rad Biol
Med -2020;152:116-41.
[70] Thuy LTT,Hai H,Kawada N.Role of cytoglobin ,a
novel radical scavenger -in stellate cell activation and
hepatic brosis -.Clin Mol Hepatol 2020; 26:280-93.
[71] Ilyasova D,Scarborough P,Spasojevic I.Urinary
biomarkers of Oxidative stress. Clin Chim Acta
[72] Damiano S,Sozio C,La Rosa G,Santillo M.NOX de-
pendent signaling dysreulation in severe COVID -19.
Clues to effective treatment.Front -Cell Inf -Microbi-
ol -2020; 10:608435.
[73] Angelico F,Loffredo L,Pignatelli P,Augelletti T,Car-
nevale R,Pacella A, et al. Weight loss is associated
-with -improved endothelial dysfunction via NOX2
–generated Oxidative stress down regulation in pa-
tients with Metabolic Syndrome.Intern Energ -Med
[74] Del Ben M,Polimeni L, Carnevale R,Bartimoccia
S,Baratta F,Nocella C, et al. NOX2 –generated Ox-
idative stress is associated -with - severity of ultra-
sound -liver steatosis - inpatients with -non alcoholic
fatty liver disease.BMC Gastroenterol -2014;14:81.
[75] Dong Y,Yuan Y.Accelerated inammation and Oxida-
tive stressinduced by LPS in acute lung injury.:inhi-
bition by ST1926. Int J Mol Med -2018;41(5):3405-
[76] Loffredo L,Zicani AM,Perri L, Carnevale R,Nocella
C, Angelico F, et al.Does Nox2 over activation in
children with Nonalcoholic fatty liver disease? Anti-
oxid -Redox Signal -2019;30:1325-330.
[77] Kim SY, Jeong JM,Kim SJ,Seo W, Kim MH,Choi
WM, et al. Proinflammatory Hepatic Macrophages
generate ROS -through NADPH-oxidase -via endo-
cytosis of -monomeric - TLR4-MD2 complex.Nat
Commun2017 ;8:2247.
[78] Buzzzetti E, Pinzani M, Tsochatzis EA . The multiple
hit pathogenesis of Nonalcoholic fatty liver disease
(NAFLD). Metab Clin Exp 2016; 65: 451-64.
[79] Chalasani N, Younossi ZM, Lavine AE, Diehl
AM,Brunt EM,Cusi K, et al. American Gastroenter-
ological - Association, American -Association for
thestudy of - Liver disease, American -Association
forGastroenterology;The diagnosis and management
of -non alcoholic fatty liver disease:practice guide-
lines -by the American Gastroenterological - Associ-
ation, American -Association for thestudy of - Liver
disease, American -Association forGastroenterology.
Gastroenterology 2012;142:1592-609.
[80] Tziomalos K,Athyros VG,KaragiannisA. Nonalco-
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
holic fatty liver disease in type2 Diabetes: pathogen-
esis -and treatment options. -Curr Vasc Pharmacol -
[81] Kulvinder Kochar Kaur, Gautam Allahbadia,
Mandeep Singh . ’Attempt to utilize Classification
of Type2 Diabetes mellitus subgroups provided by
Ahlqvist to generate individualized treatment meth-
ods based on the actions on insulin resistance & βcell
function :A move forward to more effective diabetes
control from start &avoid End StageDamage ‘’.2021
Under review.
[82] Dasarathy S, Dasarathy J,Khayami A,Yerian LM,Ser-
gent R,McCollough AJ. Randomized controlled trial
-of omega3 fatty acids -in the - treatment - of non al-
coholic steatohepapititis -in type2 Diabetes mellitus.
Hepatology 2013; 58:518a.
[83] Alam F,Islam MA,Mohammed M,Ahmad I,Kamal
MA,Donelly R, et al. Efficacy and safety of Piogl-
itazone monotherapy in type2 Diabetes mellitus.:a
systematic review and -meta-analysis of Randomized
controlled trials.Sci Rep -2019;9:5389.
[84] Lebovitz HE. Thiazolidenediones :The forgotten Di-
abetic medications .Curr -Diab Rep 2019;19:151.
[85] Schernather G,Currie CJ, Schernather GH.Do we still
need Pioglitazone for the treatment - of type2 Diabe-
tes mellitus?a risk benet critique in 2013. Diabetes
Care 2013; 36:S155-S161.
[86] Vieira R,Souto SB,Sanchez-Lopez E,Machado
AL,Severino P,Jose S, et al. Sugar lowering drugs
for -type2 Diabetes mellitus and Metabolic Syn-
drome-review of classical and newcompounds.
Pt1-Pharmaceuticals -2019;12:152.
[87] Tyagi SM,Gupta P,Sai niAS,Kaushal C,Sharma S.The
Peroxisome Proliferator adenineActivated Receptor:a
family of nuclear -Receptors --role in various diseas-
es.J Adv Pharm Technol Res 2011;2:236-40.
[88] Choi SS,Park J, Choi JH.Revisiting PPAR -as
a target -for the treatment of Metabolic disorders
.BMB Rep - -2014;47:599-608.
[89] Fonseca V.Effect of thiazolidenediones on body
-weight -in patients type2 Diabetes mellitus.Am J
Med -2003;115:42S-48S.
[90] Kang JG,Park CY.The actions of -PPAR -γ -ago-
nists on the various -target organs .Korean J Obes
[91] Kawai T,Funae O,Shimada A,Tabata -M,Hirata T,At-
sumi Y, et al. Effects of pre treatment with low dose
metformin on metabolic - parameters and -weight
gain by -Pioglitazonein Japanese -patients -with
type2 Diabetes.Int -Med -2008;47:1181-188.
[92] Musso G,Cassander M,Paschetta E,Gambino R. Thi-
azolidenediones and advanced liverfibrosis -in non
alcoholic steatohepatitis -:a meta-analysis.JAMA Int
-Med -2017;177:633-40.
[93] Bril F,Kalavalapalli S,Clark VC,Lomonaco R,Sol-
devila-Pico C,Liu IC, et al.Response to Pioglita-
zonein - patients -with -non alcoholic steatohepatitis
- with vs without type2 Diabetes. Clin Gastroenterol
Hepatol -2018;16:558-66.
[94] Yuan G,Zhang ML,Gong ZJ.Effects of PPAR –g ago-
nist Pioglitazoneon rat -hepatic brosis. World JGas-
[95] Shah RA,Kowdley KV. Obeticholic acid for the treat-
ment of non alcoholic steatohepapititis.Expert Rev
Gastroenterol Hepatol -2020;14:311-21.
[96] Verbeke L,Mannaerts I,Shierwagen R,Govaore
O,Klein S,Vander Elst I, et al.FXR against Obe-
ticholic acid reduces -hepatic inflammation and
fibrosis in a rat model of toxic cirrhosis. Sci Rep
[97] Li T,Francl JM,Boehme S,Chang JY. Regulation of
cholesterol and Bile acid homeostasis by the cho-
lesterol7α hydroxylase / steroid -response -element
binding protein 2/micro RNA-33a in mice. Hepatolo-
gy 2013; 58:1111-121.
[98] Pelliciari R, Costantino G, Camaioni E,Sadeghpour
BM,Entrena A,Willson TM, etal . Bile acid deriva-
tives -as ligands of the -Farsenoid X receptor:synthe-
sis, evaluation and structure Activity relationship -of
a series of body and side chain modified analogues
-of -chenodeoxycholic acid. J Med Chem - -2004;
[99] Mudaliar S,Henry RR,SanyalAJ,Morrow L,Marshall
HU,Kipnes M, etal .Efcacy and safety of the -Farse-
noid X receptor agonist Obeticholic acid in patients
-withtype2 Diabetes mellitus and -of -non alcoholic
fatty liver disease. Gastroenterology -2013; 145:574-
[100] Hameed B, Terrault NA,Gill RM,Loomba R, Cha-
lasani N,Hoofnage JH, etal .The NASH Clinical
research network. Clinical and metabolic effects
associated -with -weight changes -and - Obeticholic
acid in non alcoholic steatohepatitis. Aliment -Phar-
macol -Ther 2018;47: 645-56.
[101] Hindson J. Obeticholic acid for the treatment of non
alcoholic steatohepapititis. Nat Rev Gastroenterol
Hepatol 2020; 17:65.
[102] Berger J,Moller DE.The mechanisms of action of
PPARs. Annu Rev Med -2002;53: 409-35.
[103] Connolly JJ,Ooka K,Lim JK,Future Pharmacother-
apy -for non alcoholic steatohepapititis( NASH):re-
view in phase 2 and 3 trials.J Clin Transl Hepatol
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
2018; 6:264-75.
[104] Pawlak M,Lefebvre P,Staels B. Molecular mech-
anisms of PPARα action and its impact on lipid
metabolism , inammation and brosis -in non al-
coholic steatohepatitis. -J Hepatol 2015;62: 720-33.
[105] Musso G,Gambino R,Cassader M,Pagano G.A me-
ta-analysis for the randomized -trials -for the treat-
ment of non alcoholic -Fatty Acid Liver Disease.
Hepatology 2010; 52:79-104.
[106] Bojic LA,Huff MW. Peroxisome Proliferator Acti-
vated Receptorδ:A multifaceted -metabolic player.
Curr Opin Lipiodol 2013;24: 171-7.
[107] Karpe F,Ehrenborg EE.PPARδ in humans:genetic
-and Pharmacologic evidence for a signicant Met-
abolic -function. Curr Opin Lipiodol 2009;20: 333-
[108] Riserus U,Sprecher D,Johnson T,Olson E,Hirsch-
berg S,Liu A, etal. Activation of Peroxisome Prolif-
erator Activated Receptorδ( PPAR -δ)promotes re-
versal of multiple metabolic abnormalities ,reduces
Oxidative stress,and increases fatty acid oxidation
in moderately obese men. Diabetes 2008;57: 332-9.
[109] Ratziu V,Harrison SA,Francque S,Bedossa P,Lahert
P,Serfaty L, etal .GOLDEN 505 Investigator Study
Group. Elafibranor,an agonist of -the Peroxisome
Proliferator Activated Receptor α,and δ induces
resolution of non alcoholic steatohepatitis with-
out fibrosis worsening. Gastroenterology 2016;
[110] Briand F,Heymes C,Bonada L,Angles T,Charpen-
tier J,Branchereau M, etal.A 3week non alcoholic
steatohepapititis mouse model -shows Elafibranor
benefits -on hepatic inflammation and cell death.
Clin Transl Sci 2020; 13:529-38.
[111] Tolbol KS,Kristiansen MN,Hansen HH,Veidal
SS,Rigbolt KT, etal. Metabolic and hepatic effects
of Liraglutide, Obeticholic acid and Elabranor in
diet induced obese -mouse model of biopsy con-
rmed non alcoholic steatohepatitis. -World JGas-
[112] Briand F,Maupoint J, BrousseauE,Breyner
N,Bouchet M,Costard C, etal. Elabranor improves
diet induced non alcoholic steatohepatitis associat-
ed -with heart failure with preserved ejection frac-
tion -in golden Syrian hamsters. Metabolism 2021;
[113] Cariou B,Hanf R,Lambert –Porcheron S,Zair Y,Sau-
vinet V, etal.Dual Peroxisome Proliferator Activated
Receptor α,and δ agonist GFT505 improves hepatic
and peripheral insulin sensitivity in abdominally
obese -subjects. Diabetes Care 2013; 36:2923-930.
[114] Cariou B, Zair Y,Staels B,Bruckert E. Effects of -
the new dual PPARα / δ agonist GFT505 on lipid
and glucosehomeostasis in abdominally obese -
patients with combined dyslipidemia or impaired
glucose metabolism. Diabetes Care 2011; 34:2008-
[115] Jeong SW. Non alcoholic fatty liver disease:A
Drug revolution is coming. Diabetes Metab J
[116] Irruarrizaga-Lejarreta M,Varela –Rey M, Fernan-
dez-RamosD, Martinez-A rranz I,Delgado TC, etal.
Role of Aramchol in steatohepapititis and - -brosis
in mice . Hepatol Commun2017;1: 911-27.
[117] Dobrzyn A,Ntambi JM. Stearoyl-Co A Desatu-
rase as a new drug for obesity treatment. ObesRev
[118] Goldiner I,Van der Velde AE,Vandenberghe KE,Van
wijland MA,Halpern Z,Gilat T, etal.ABCA1 – de-
pendent but apoA1 independent - cholesterol efux
-mediated by fatty acids -bile acid conjugates(-
FABACs).Biochem J 2006;396:529-36.
[119] Safaldi K,Konikoff FM,Mahmaid M,Zelber –Sagi
S,Halpern N,Gilat T etal.The fatty acids -bile acid
conjugate Aramchol reduces liver fat content in
Non Alcoholic Fatty Acid Liver Disease. Clin Gas-
troenterol Hepatol 2014; 12:2085-91.
[120] Gentiella R,Pechtner V,Corcos A,Consoli A. Glu-
cagon like peptide 1 receptor -agonists in type2 -
Diabetes treatment :are they all the same? Diabetes
-Metab Res Rev 2019; 35:e3070.
[121] Greiner TU,Backhed F.Microbial regulation
of GLP-1 and L-cell biology . -Mol Metab
[122] Michalowska J,Miller-Kasprzak E,Bogdanski P. In-
cretin -hormones in obesity -and related cardiomet-
abolic disorders;the Clinical perspective. Nutrients
[123] Armstrong MJ,Gaunt P,Aithal GP,Barton D,Hull
D,Parker R, etal .LEAN trial team .Liraglutidesafe-
ty and efficacy in for patients with non alcoholic
steatohepatitis(LEAN):a multicenter ,double blind-
ed , a -randomized,placebo- controlled -phase 2
-study . Lancet 2016; 387:679--90.
[124] DeFronzo RA,Ratner R,Han J,Kim D,Fineman M
etal. Effects of Exenatide ( Extendin-4)on glycemic
control and weight control over 30weeks in met-
formin treated patients with type2 - Diabetes. Dia-
betes Care 2005; 28:1092-100.
[125] Crane J,McGowan B.The GLP-1 agonists, Lira-
glutide,as a pharmacotherapy for obesity.Ther Adv
Chronic Dis - 2016; 7:92-107.
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
[126] Davies MJ,Aronne LJ,Caterson ID,Thomsen AB,Ja-
cobsen PB,Marso SP. Liraglutide and cardiovascular
outcomes -in adults for obesity:a posthoc analysis
from the SCALE -Diabetes randomized controlled
trials. Diabetes Obes Metab 2018;20:734-39.
[127] AdamsJM,Pei H,Sandoval DA,SeelyRJ,Chang RB,-
Liberles SD, etal. Liraglutide modulates appetite
and body weight through Glucagon like peptide 1
receptor -expressing glutamatergic neurons. Diabe-
tes -2018;67:1538-48.
[128] Mantovani A,Petracca G,Beatrice G,Csermely
A,Lonardo A,Targher G. Glucagon like peptide 1
receptor -agonists for treatment of Non Alcoholic
Fatty Acid Liver Disease and Non Alcoholic steato-
hepapititis:an updated meta-analysis of randomized
controlled trials. Metabolites -2021;11:73.
[129] Kapodistria K,Tsilibary EP,KotsopouloE,Moustar-
das P,Kitsiou P. Liraglutide,A human Glucagon like
peptide 1 analogue ,stimulates AKT dependent -sur-
vival signaling.J Cell Mol Med 2018;22:2970-980.
[130] HeQ,Sha S,Sun L,Zhang J,Dong M. GLP-1 an-
alogueimproves - hepatic lipidaccumulation by
inducing -autophagy via AMPK/ mTOR pathway.
Biochem -Biophys Res Commun -2016;476:196-
[131] Chalasani N, Younossi ZM, Lavine AE, Diehl
AM,Brunt EM,Cusi K,Sanyal AJ. The diagnosis
and management of -non alcoholic fatty liver dis-
ease:practice guidelines -by the American Gas-
troenterological - Association, American -Asso-
ciation for thestudy of - Liver disease, American
-Association forGastroenterology. Hepatology
[132] Nelson CH,Etchevers K,Yi S,Breckenridge
D,Hepner M,Patel U etal.Pharmacokinetic ,safety
and tolerability of Selonsertib,an apoptosis signal
regulating kinase 1(ASK1) Inhibitor), following
first -in human single and multiple ascending
doses in healthy subjects.Clin Pharmacokinet
[133] Budas G,Karnic S,Johnson T,Shadeh T,Watkins S
, Breckenridge D, etal. Reduction of Liver steato-
sis and brosis -with an ASK1 Inhibitor in murine
model of NASH is accompanied by improvements
in cholesterol, the bile acid and lipid metabolism.J
Hepatol -2016;64:S170.
[134] Loomba R, Lawitz EJ,Mantry PS, Jayakumar A,
Caldwell SH,Arnold H etal.The - ASK1 Inhibitor
Selonsertib in - patients with Non Alcoholic steato-
hepapititis:a randomized phase 2 - trial. Hepatology
[135] Dickson I.No antifibrotic effects of Selonsertib
in NASH. Nat Rev Gastroenterol Hepatol 2020;
[136] Puente A,Fortea JL,Cabezas J,Arias Loste
MT,Iruzubieta P,Llerena S, etal.LOXL2;A new
target in antifibrogenic therapy. Int J MolSci
[137] Rodriguez HM,Vaysberg M,Mikels A,McCauley
S,Velayo AC,Garcia C, etal.Modulation of lysyl
oxidase –like 2 enzymatic activity by an allosteric
antibody Inhibitor.J Biol Chem 2010;285:20964-
[138] Lipson KE,Wong C,Teng Y,Spong S.CTGF is a cen-
tral mediator of tissue remodeling and its inhibition
can reverse the brosis.Fibrogenesis T issue Repair
2012;5:S 24.
[139] Harrison SA, Abdelmalek MF, Caldwell SH,Shiff-
man ML, Diehl AM,Ghalib R etal.Simutuzumab
-is ineffective for patients with bridging brosis or
compensated cirrhosis caused by ) -non alcoholic
steatohepapititis. Gastroenterology 2018;155:1140-
[140] Marra F, Tacke F.Roles of chemokines - in liver dis-
ease. Gastroenterology 2014;147:577-94.
[141] Kim BM,Abdelfattah AM,Vasan R,Fuchs BC,Choi
MY. Hepatic Stellate cells -secrete Cc15 to induce
hepatic steatosis.Sci Rep 2018;8:7499.
[142] Friedman SL, Sanyal AJ, Goodman SM, Lefebvre
E,Gottwald M,Fischer L, Ratziu V.Efficacy and
safety -study of cenicriviroc for treatment of -non
alcoholic steatohepatitis in adult subjects with Liver
brosis:CENTAUR Phase 2b study design.Contemp
Clin Trials2016; 47:356-65.
[143] Friedman SL, Ratziu V,Harrison SA, Abdelmalek
MF, Aithal GP,Caballeria J, etal .A randomized,pla-
cebo- controlledtrial of cenicriviroc for the treat-
ment of -non alcoholic steatohepatitis with brosis.
Hepatology 2018; 67:1754-67.
[144] Anstee QM,Neuschwander –Tetri BA,Wong VW,
Abdelmalek MF, Younossi ZM,Yuan J, etal. - Ceni-
criviroc for the treatment of -liver brosis in adults
with - of -non alcoholic steatohepatitis:AURORA
phase 3 -study design. Contemp Clin Trials2020;
[145] Boutari C,Perakakis N,Mantzoros CS. Association
of Adipokines with development of , non alcoholic
fatty liver disease.Endocrinol Metab 2018;33:33-
[146] Polyzos SA,Kountouras J, Mantzoros CS.Leptin
in non alcoholic steatohepatitis:a narrative review.
Metabolism -2015;64:60-78.
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
[147] Jamali R,Arj A,Razavizade M,Aarabi MH.Pre-
diction of non alcoholic fatty liver disease via
a novel panel of serum Adipokines.Medicine -
[148] Polyzos SA,Kountouras J,Anastasilakis AD,Geldari
EV, Mantzoros CS. Irisin in -patients -with
-non alcoholic fatty liver disease . Metabolism
[149] Zhang SR,Fan ZM. Ghrelin- ghrelin-O-Acetyl
transferase system -in the pathogenesis of non
alcoholic fatty liver disease. World J Gastroenter-
[150] Arvaniti VA,Thomopoulos KC,Tsamandas A,Makri
M,Psyrorogiannis A,Vafiadis G, etal .Serum adi-
ponectin -levels in different types of non alcoholic
fatty liver disease: correlation with - -steatosis,necro
inammation and -brosis.Acta Gastroenterol Belg
[151] Garinis GA,Fruci B,Mazaa A,DeSienna M,Abe-
navoli A,Gulletta E, etal.Metformin -versus dietary
-treatment of -non alcoholic steatohepatitis.Int J
Obes -2010;34:1255-64.
[152] Ryan MJ,Dudash HJ,Docherty M,Geronilla KB,-
Baker BA,Haff GG, etal. Vitamin E and Csup-
plementation -reduces Oxidative stress improves
antioxidant tenzymes -and positive muscle work
-in chronically loaded muscles -of aged rats .Exp
Gerontol -2010;45:882-95.
[153] Balmer ML,Siegrist K,Zimmermann A,Dufour
JF.Effect of ursodeoxycholic acid in combination
with Vitamin E on Adipokines and apoptosis in pa-
tients with non alcoholic steatohepatitis. Liver Int
-2009; 29:1184-88.
[154] Otabe S,Yuan X,Fukutani T,Wada N,Hashinaga
T,Nakayama H, etal.Over expression of human
-adiponectin -in transgenic mice - results in suppre
ssion of fat accumulation and prevention of prema-
ture death -by high calorie diet. Am J Physiol Endo-
crinol Metab -2007;293:E210-E218.
[155] Sharma D,Wang J,Fu PP, Sharma S,Nagalingam
A,Mells A, etal. Adiponectin antagonizes the onco-
genic actions of leptin in Hepatocellular carcino-
genesis. Hepatology 2010; 52:1713-22.
[156] Kelesidis T, Kelesidis I,Chou Z, Mantzoros CS.Nar-
rative review:The role of leptin in human -physiolo-
gy:emerging Clinical applications .Ann Intern Med
[157] Unger RH.Lipotoxic diseases, Annu -Rev Med
[158] Ikejima K,Honda H,Yoshikawa M,Hirose M,Kita-
mura T,Takei Y, etal.Leptinaugments inflammato-
ryand probrogenic -responses in the murine liver
induced by hepatoxic chemicals. Hepatology 2001;
[159] Polyzos SA,Aronis KN,Kountouras J,Raptis
DD,Vasiloglu MF, Mantzoros CS. Circulating
leptin in non alcoholic fatty liver disease:a sys-
tematic review and -meta-analysis. Diabetologia -
[160] Muse ED,Obici S,Bhanot S,Monia BP,McKay
RA,Rajala MW, etal.Role of resistin -in diet in-
duced hepatic insulin resistance.J Clin Invest -2004;
[161] Bertolani C,Sancho Bru P,Failli P,Batallier R,Alef-
fi S,DeFranco R, etal. Resistin as an intra hepatic
cytokine : Over expression during chronic injury
and induction of proinammatory action in -hepatic
stellate -cells.Am J Pathol -2006; 169:2042-53.
[162] Jamali R, Razavizade M, Arj A,Aarabi MH. Serum
adipokines might predict liver histology ndings -in
- non alcoholic fatty liver disease. World J Gastro-
[163] Rasouli N,Yao-BorengaaserA,Miles LM,Elbe-
in SC,Kern PA.Increased plasma Adiponectin in
response to Pioglitazone does not result from In-
creased gene expression . Am J Physiol Endocrinol
Metab -2006;290:E42-E46.
[164] Delporte C. Structure -and physiological actions of
-ghrelin.Scientica 2013; 2013:518909.
[165] Purnell JQ,Weigle DS,Breen P,Cummings DE.
Ghrelin levels correlate with insulinlevels, insulin
resistance,and high density lipoprotein cholesterol
,but not with gender ,menopausal status -or cor-
tisol -levels in humans. J Clin Endocrinol Metab
[166] LiY,Hai J, Li L,Chen X,Peng H,Cao M, etal. Ad-
ministration -of Ghrelin improves inflammation,
Oxidative stress,and apoptosis during -and after non
alcoholic fatty liver disease development.Endocrine
[167] Mao Y,Cheng J,YuF,LiH,GuoC,Fan X. Ghrelin at-
tenuated lipotoxicity via autophagy induction .Cell
Physiol Biochem -2015;37:563-76.
[168] Schnyder S,Handschin C. Skeletal muscle as an en-
docrine organ:PGC-1α,myokines and exercise.Bone
[169] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.
Therapeutic Applications of the Recent Understand-
ing of Brown or “Beige” Adipocyte Physiology.
Adv Tech Biol Med -2015; 3: 128.
DOI: 10.4172/2379-1764.1000128.
[170] Zhang Y,Li R,Meng Y,LiS,Donelan W,Zhao Y,
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
etal. Irisin stimulates browning of white adipocytes
through -mitogen activated protein kinase p38MAP
Kinase and ERKMAP Kinase Signaling. Diabetes
[171] Polyzos SA,Mathew H, Mantzoros CS. Irisin:A true,
circulating hormone. Metabolism 2015;64:1611-18.
[172] Perez –Soleto D,Roca –RivadaA,BaamondeI,Bal-
tar J,Castro AI,Dominguez E, etal.Lack of adipo-
cytes-Fndc5/ Irisin expression -and secretion re-
duces thermogenesis and enhancesadipogenesis.Sci
Rep -2017;7:16289.
[173] Muir AJ,Levy C,Janssen HLA,Montano-Loza AJ,-
Shiffman ML, Caldwell S, etal. Simutuzumab for
primary - sclerosing -cholangitis: phase 2 study
results with insights -on the natural history of -dis-
ease. Hepatology 2019; 69:684-98.
[174] Chen P,Chung FM,Chang DM,Tsai JC,Huang
HF,Shin SJ, etal.Elevated plasma levels of visfatin/
preB cell colony-enhancing factor in treated pa-
tients with type2 - Diabetes. -J Clin Endocrinol Me-
tab -2006;91:295-9.
[175] Mousavi Z,Ganji A,Farrokh Tehrani D,Bahari A,Es-
meil Zadeh A,Delghadi M. Correlation of visfatin-
levels with non alcoholic fatty liver in Metabolic
Syndrome.J Islam Republic Iran 2017;31:28.
[176] KadoglouNP, Tsanikidis H,Kapelozou A,Vrabas
I,Vitta I,Krayannacos PE, etal.Effect of -ofrosiglita-
zone -and metformin treatment - on apelin, visfatin
ghrelin levels in -patients with type2 - Diabetes
.Metabolism 2010;59:373-79.
[177] Kim E,Voatour P. Hepatocellular carcinoma:Old
friends and new tricks.Exp Mol Med2020; 52:1898-
[178] CholankerilG,Patel R,,Khurana S,Satapathy SK.
Hepatocellular carcinoma in non alcoholic steato-
hepatitis:current -knowledge and implications for
management. World JHepatol 2017; 9:-533-43.
[179] Jing YY,Han Z,Sun K,Zhang SS,Hou J,Liu Y, etal.
Toll like receptor 4 signaling promotes epithelial –
mesenchymal transition in human - Hepatocellular
carcinoma induced by lipopolysaccharides.BMC
Med 2012;10:98.
[180] Li H, Li Y, LiuD, LiuJ.LPS promotes epithelial –
mesenchymal transition and activation of -TLR4/
JNK signaling.Tumor -Biol -2014;35:10429-35.
[181] Gupta H,Youn GS,Shin MJ,Suk KT. Gut micro-
biota in Hepatocarcinogenesis. Microorganisms
[182] Saxena NK,FuPP,Nagalingam A, Wang J,Handy
J,Cohen C, etal. Adiponectin modulates -c –jun N
terminal kinase -and mammalian target of rapamy-
cin -and inhibits Hepatocellular carcinoma. Gastro-
enterology -2010;139:1762-73.
[183] Al-Gayyar AM,Abbas A,Hamdan AM.Chemopre-
ventive -and hepatoprotective -role of Adiponect-
in(SULF2 Inhibitor) in Hepatocellular carcinoma.
Biol Chem 2016;397:257-67.
[184] Kamada Y,Matsumoto H,Tamura S,Fukushima J,Ki-
so S,Fukui K, etal.Hypo Adiponectinemia acceler-
ates hepatic tumorformation - -in non alcoholic ste-
atohepatitis mouse model.J -HepatoL -2007;47:556-
[185] Shen J,Yeh CC,Wang Q,Gurvich I,Siegel AB, etal.
Plasma Adiponectin and Hepatocellular carcinoma
survival -among patients without liver transplanta-
tion.Anticancer Res 2016;36:5307-14.
[186] Wei R,Hu Y,Dong F,Xu X,Hu A,Gao G. Hepatoma
-cell-derived leptin down regulates -the immu-
nosuppressive function of regulatory T cells -to
enhance the anti tumor activity of CD 8+T cells
-.Immunol Cell Biol -2016;94:388-99.
[187] Stefanou N,Papanilkolaou V,Furukawa Y,Nakamura
Y,Tsezou A. Leptin as acritical regulator of Hepa-
tocellular carcinoma development through modu-
lation of human telomerase -reverse transcriptase.
BMC Cancer -2010;10:442.
[188] Levielle M,Estall JL. Mitochondrial dysfunctionin
the transition - from -NASHto HCC. Metabolites
[189] Nakagawa H,Umemura A,Taniguchi K,Font –Bur-
gada J,Dhar D,Ogata H, etal.ER Stress -cooper-
ates with hypernutrition to trigger TNF dependent
-spontaneous HCC development. Cancer Cell -
[190] Von Loeffelholz H,Horn P,Birkenfeld AL,Claus
RA,Metzing BU,Docke S, etal.Predictor of liver fat
-in preoperative patients with non alcoholic fatty
liver disease. J Invest Surg -2016;29:266-74.
[191] Peter A,Kovarova M,Staiger H,Mechann J,Schick
F,Konigsrainer A, etal.The Hepatokines Fetuin A
and -Fetuin B -are upregulated in the state of hepat-
ic steatosis and may differently impact -on glucose-
homeostasis in humans. Am J Physiol Endocrinol
Metab -2018;314:E266-E273.
[192] Cui Z,Xuan R,Yang Y.Serum Fetuin A level is as-
sociated -with non alcoholic fatty liver disease in
Chinese population.Oncotarget -2017; 8:-107149-
[193] Mukhuty A,Fouzder C,Mukherjee S,Malick C,Muk-
hopadhyay S,Ray S, etal. Fetuin A secretion from
Pancreatic βcells - -adversely affects -its function
and elicits inflammation. Biochem -Biophys Res
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
Commun -2017;491:1118-24.
[194] -Dasgupta S,Bhattacharya S,Biswas A,Majum-
dar SS, Mukhopadhyay S,Ray S, etal. -Nuclear
factor kappa Bmediates -lipid-induced Fetuin A
expression in hepatocytes -that improve adipocyte
-function effecting insulin resistance.Biochem J -
[195] Mori K,Emoto M, Araki T,Yokoyama H,LeeH
,Taramura M, etal. -Effects of Pioglitazone on Se-
rum Fetuin A levels -in -patients with type2 - Dia-
betes. Metabolism 2008;57:1248-52.
[196] Ochi A, Mori K,Emoto M, Nakatani N, Morioka
T,Motoyama K, -etal.Direct inhibitory -Effects of
Pioglitazone on -hepatic -Fetuin A expression.PLoS
One -2014;9:e88704.
[197] Li L,Gu X,Fang M,JiJ,YiC,Gao C.The diagnostic
value of Serum fucosylated Fetuin A in hepatitis
Bvirus related liver diseases. Clin - Chem LabMed
[198] Pan X,Kaminga AC,Chen J,Luo M, LuoJ. Fetuin A
and -Fetuin B - in non alcoholic fatty liver disease:a
meta-analysis and -meta regression. Int JEnviron
Res -Public Health2020;17:2735.
[199] Meex RC,Hoy AJ,Morris A,Brown RD,LoJC,Burke
M, etal. -Fetuin B -is a -secreted hepatocyte factor
-linking steatosis to impaired glucose metabolism.
Cell Metab 2015;22:1078-89.
[200] Zhou W, Yang -J,Zhu J, Wang -Y,Wu Y,Xu L, etal.
-Fetuin B - aggravates -liver X receptor mediated
-hepatic steatosis -through AMPK in Hep G2 cells
in mice .Am J Transl Res -2019;11:1498-1509.
[201] Ebert T,Linder N,Schaudinn - A,Busse H,Berger
J,Lichtinghagen R, etal. -Association of -Fetuin B -
with markers of liver brosis in non alcoholic fatty
liver disease .Endocrine 2017;58:246-52.
[202] Zhong G,Kirkwood J,Won KJ,Tjota N,Jeong H,Iso-
herranen N. Characterization of Vitamin A me-
tabolome -in human livers with and -without non
alcoholic fatty liver disease.J Pharmacol -Exp Ther
2019;370: 92-103.
[203] Perduca M,Nicolis S.Mannuci B,Galliano M,Mo-
naco HL.Human plasma Retinol Binding protein
-4(RBP4) is also a fatty acid Binding protein.
Biochim -Biophys Acta Mol Cell Biol Lipids
2018;1863:458 -66.
[204] Wang X,Chen X, Zhang H,Pang J,Lin J, Xu X, etal.
Circulating -Retinol Binding protein 4is associated
-with development -and regression of non alcoholic
fatty liver disease. Diabetes Metab 2020;46: 119-
[205] Graham TE, Yang Q,Bluher M,Hammarstedt A,Ci-
araldi TP,Henry RR, etal. Retinol Binding protein
4 and insulin resistance in lean ,obese and diabetic
-subjects. NEngl J -Med 2006;354:2552-63.
[206] Petta S,Tripodo C,Grimaudo S,Cabibi D,Camma
C,DiCristina A, etal.High liver RBP4 protein con-
tent -is -associated -with histological features in
patients with genotype1 chronic hepatitis C and
with non alcoholic steatohepatitis. Dig -Liver Dis
[207] Bahr MJ,Boeker KH,Manns MP,Tietge UJ.De-
creased hepatic - RBP4 -secretion -is correlated
with - -reduced levels -hepatic - glucose -production
but is not -associated -with insulin resistance in pa-
tients with cirrhosis.Clin -Endocrinol -2009;70:60-
[208] Hara H,Uchida S,Yoshi mura H.Aoki M,Toyoda
Y,Sakai K, etal.Isolation and -Characterization ofa
novel liver specific gene, Hepassocin,upregulated
-during liver regeneration. Biochim -Biophys Acta
[209] Abdelmeomen G,Khodeir S,Zaki AN,Kasaab
M,Abou Saif S,Abd Elasam S.Over expressionof
-Hepassocin in diabetic -patients with non alcoholic
fatty liver disease may facilitate increased -hepatic
lipid accumulation. Endocrin Metab Immune Dis-
ord Drug Targets - 2019;19: 185-8.
[210] Wu HT,Lu FH,OuHY,Su YC,Hung HC, Wu JS, etal.
The role of Hepassocin in the development of non
alcoholic fatty liver disease. -J Hepatol 2013;59:
[211] Cheng KP, OuHY, Hung HC,LiCH,Fan KC, Wu JS,
etal. Unsaturated fatty acids increase the expression
of Hepassocin through a Signal -Transducers and
Activators of Transcription3 dependent pathway in
HepG2 cells.Lipids - 2018;53:863-69.
[212] Jung TW, Chung YH,Kim HC, Abd -El-Aty AM,
Jeong JH.Hyper lipidemia-induced -Hepassocin in
the liver contributes -to insulin resistance in skeletal
muscle. - MolCell Endocrinol2018; 470:26-33.
[213] YuHT, Yu M,Li CY,Zhan YQ,Xu WX, Li -YH ,
etal. Specic - expression of -and regulation -of He-
passocin - in the liver and down regulation -of the
correlation of -HNF1 alpha with decreased levels of
Hepassocin in human Hepatocellular carcinoma. J
Biol Chem 2009;284:133335-1313347.
[214] Li CY,Cao CZ, Xu WX, Cao MM, Yang F,Dong
L, etal. Recombinant human -Hepassocin -stimu-
lates -proliferation of hepatocytes -in vivo and im-
proves survival -in -Hepatocellular carcinoma.Gut -
[215] Yan J, Yu Y, Wang N, Chang Y,Ying H, Liu W, etal.
Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0
LFIRE1/HFREP-1,a liver Specific - gene is fre-
quently -down regulated and has growth suppressor
activity in Hepatocellular carcinoma. Oncogene
[216] Pan J,Parlee SD,Brunel FM, Li P,LuW,Perez-Tilve
D, etal.Optimization of peptide inhibitors of
β-Klotho as antagonists of Fibroblast -growth
-factor 19 and -21.ACS Pharmacol Transl Sci
[217] Wu AL,Coulter S,Liddle C,Wong A,Eastham-An-
derson J,French DM, etal.FGF19 regulates cell
proliferation, glucose and bile acid metabolism
via FGFR4 -dependent and independent pathways.
PLoS One -2011;6:e17868.
[218] Jiao N,Baker SS,Chapa-Rodriques A, Liu W,Nu-
gent CA,Tsompana M, etal.Suppressed hepatic
bile acid signaling despite elevated production of
primary -and secondary bile acids in NAFLD.Gut
[219] Li Y,Zhang W,Doughtie A,Cui G, Li X,Pandit H,
etal.Upregulation of Fibroblast -growth -factor 19
and its receptor associates -with -progression from
-fatty liver to Hepatocellular carcinoma. Oncotarget
-2016; 7:-52329-52339.
[220] Chen L, Liu H, Liu J,Zhu Y,Xu L,HeH, etal.Klotho
endows hepatoma cells -with resistance to anoikis
-via VEGFR 2/PAK1 activation in -Hepatocellular
carcinoma. PLoS ONE -2013;8:e58413.
[221] Gong Q,HuZ, Zhang F,Cui A, Chen X,Jiang H, etal.
Fibroblast -growth -factor 21 improves insulin sen-
sitivity by inhibiting mammalian target of rapamy-
cin complex1 in mice . Hepatology 2017; 64:425-
[222] Hong ES,Lim C,Choi HY,Lee YK.KuEJ,Moon JH,
etal.Plasma of Fibroblast -growth -factor 21 levels
increase with ectopic fat accumulation -and its re-
ceptor levels -are decreased in the visceral fat of in
-patients with type2 - Diabetes .BMJ Open Diabetes
Res Care 2019;7:e00076.
[223] Flisiak-IackiewiczM, Bobrus-Chociej A, Wasilews-
ka M, Tarasow E,WojtowskaM, Lebenszejn DM.
Can Hepatokines be regarded as novel noninvasive
serum biomarkers -of intraHepatic liver -content in
obese -children?Adv Med Sci -2019;64:30484.
[224] Rusli F,Deelen J,Andriyani E,Boekschoten MV,Lute
C,Van den Akker EB, etal. Fibroblast -growth
-factor 21 reects liver fat accumulation - and dys-
regulation of signaling pathways in the liver -of
C57BL/6J mice.Sci Rep - 2016; 6:30484.
[225] Yang M,Xu D, Liu Y,Guo X, Li W, Guo C, etal.
Combined serum -biomarkers in noninvasive -diag-
nosis of non alcoholic steatohepapititis. PLoS ONE
[226] Yang C, Lu W,Lin T,You P,YeM,Huang Y, etal. Ac-
tivation - of liver FGF21 -in Hepatocarcinogenesis
and during Hepatic stress .BMC -Gastroenterol
2013; 13:67.
[227] Kong FJ,MaLL,LiG,Chen YX,Zhou JQ,Circulating
betatrophin levels an d gestational Diabetes melli-
tus:a systematic review and -meta-analysis -. PLoS
ONE -2017;12:e016994.
[228] Lee YH, Lee SG, Lee CJ,Kim SH,Song YM,Yoon
MR, etal. Association between betatrophin/
ANGPTL8 and non alcoholic fatty liver disease:an-
imal and human studies. Sci Rep - 2016; 6:24013.
[229] Zhang R.The -ANGPTL3-4-8 model ,a molecular
-mechanism for triglyceride trafcking .Open Biol
-2016; 6:150272.
[230] Yin Y,Ding X,Peng L,Hou Y,Ling Y,GuM, etal.In-
creased serum ANGPTL8 concentrations in patients
-with pre Diabetes and -type2 - Diabetes.J Diabetes
Res 2017; 2017:8293207.
[231] Gusarova V,Alexa CA,Na E,Stevis BE,Xin Y,-
Bonner-Weir S, etal. ANGPTL8/ betatrophin does
notcontrol Pancreatic βcells - expansion.Cell -2014;
[232] Zhang L,Shannon CE, TM,Abdul –Ghani MA,-
Fourcaudot M,Norton L.Regulation of ANGPTL8
in liver -and adipose tissue by nutritional and
hormonal signals and the effect on glucosehom-
eostasis in mice. Am J Physiol Endocrinol Metab
[233] Chen YQ,Pottanat TG,Siegel RW,Ehsani M,Qian
YQ,Zhen EY, etal. Angiopoietin –Like Protein- 8
differentially regulates ANGPTL 3 and ANGPTL
4 during postprandial -partitioning of fatty acids.J
Lipid Res - 2020;61:1203-20.
[234] Dijk W,Kersten S.Regulation of -Lipid metabolism
by Angiopoietin –Like Protein’s . Curr Opin Lipi-
odol 2016;27: 249-56.
[235] Yoshida K,Shimizugawa T,Ono M,Furukawa H.
Angiopoietin –Like Protein 4 is a potent hyperlipid-
emia-inducing factor in mice and inhibitor of lipo-
protein lipase. J Lipid Res - 2002;43:1770-72.
[236] Ng KT,Xu A,Cheng Q,Guo DY,Lim ZX,Sun CK,
etal. Clinical relevanc e -and therapeutic potential
-of -Angiopoietin –Like Protein 4 in Hepatocellular
carcinoma.Mol Cancer 2014;13:96.
... Additionally, genetic proof pointed to NAFLD manipulated dyslipidemia is the key factor for the enhancement of risk of CVD [9]. Whereas numerous genetic polymorphism areas along with mutations possess the correlation with CVD [10] as well as NAFLD [11], certain NAFLD resulting in facilitation of Single nucleotide polymorphisms (SNP) have been detailed as resulting in reduction of risk of CVD [12,13].Other workers nevertheless did not observe such protection [14].Having reviewed the various probable etiologies of NAFLD/NASH along with potential therapies [15][16][17][18][19][20][21][22][23][24][25][26] here we decided to update on the association of NAFLD along with generation of heart diseases in NAFLD/NASH we decided to carry out a systematic review. ...
... Presently no pharmacological treatments with regards to NAFLD/ NASH has received approval .The treatments that are present have the objective of resulting in reduction of accrual of liver lipids,cause stimulation of metabolic pathways in addition to reduction of liver damage .The major classes of these medicines are i) Bile acid pathway with metabolism modulatorsii) Peroxisome Proliferator Activated Receptor (PPAR )-agonist like Elafibranor b)Lanfibranoriii)welldescribed drugs for T2mlike Glucagon like peptide 1(GLP-1) Receptor agonist-Semaglutide [128], iv)Thyroid hormone Receptor βagonist(THR-β-agonist) like Resmetriom(MGL-3196B)VK2809[rev by us in ref [25,26]'seefig 5). ...
Full-text available
Non alcoholic fatty liver disease(NAFLD) is a rapidly escalating disorder which impacts a large population worldwide. Nevertheless, cardiovascular disease(CVD) represents the biggest etiology for mortality with regards to patients of NAFLD. Atherogenic dyslipidemia, possessing the properties of plasma hypetriglyceridemia , enhancement of small dense (low density lipoproteins)LDL's particles in addition to reduction ofhigh density lipoproteins cholesterolHDL-C) concentrations are generally seen in patientswith a presentation of NAFLD.Thus here we conducted a systematic review utilizing search engine pubmed,google scholar ;web of science ;embase; Cochrane review library utilizing the MeSH terms like NAFLD; CVD; atherosclerosis; insulin resistance(IR); NASH; chronic heart failure; dyslipidemia;hepatokines; endothelial impairment; proinflammatory cytokines; FA's oxidation ; SREBP1c; ChREBP; Sirtuin; LKB1;lipogenesis; mitochondrial lipid β oxidation;genetic mutationsfrom 2010 to 2022.We found a total of 500 articles out of which we selected 143 articles for this review.No meta-analysis was done.Thus here we have detailed the more recent genetic corroboration, with provision of distinctive type of metabolic pathways implicated in NAFLD pathogenesis. Assessment of the genetic results that are accessible pointed that the crucial processthat correlated NAFLD modulated dyslipidemia, along with escalation of risk of CVD implied is the changes in the handling of fatty acids β oxidation in the liver mitochondria. NAFLD correlated genes possessing reported anti atherosclerotic or cardio protective actions in addition to existent Pharmacologic approaches that are concentrated on tackling both treatment of NAFLD in addition to reducing the risk of CVD .Further research demonstrates that inhibitors of de novo'' lipogenesis (DNL)might prove to be of benefit.
... This review subsequent to our earlier endeavours to elucidate the association of GM dysbiosis alongwith microbial metabolites alterations in NAFLD besides NAFLD/ NAFLD-HCC,the role of intestinal epithelial barrier besides the part of altered gut-liver axis associated with intestinal GM dysbiosis in generating neurodegenerative diseases(NDD), neuropsychiatric diseases(NPD) [16][17][18][19][20][21][22][23][24][25][26][27][28][29]here we attempt to further elaborate on the part of gut-liver axis alongwith their correlation with NAFLD as an update of what had been earlier described . Additionally, how to generate strategiesfor NAFLD that are dependent on microbes. ...
Full-text available
Non alcoholic fatty liver disease(NAFLD)is believed to be amongst the maximum Prevalent chronic liver disease globally secondaryto pacey escalating obesity, type 2 Diabetes mellitus(T2DM), metabolic syndrome(MetS). In the form of a hepatic presentation of a metabolic disease NAFLD initiates with hepatic accrual along with propagation towards hepatic inflammation;namely,non alcoholic steatohepatitis (NASH), hepatic fibrosis/ cirrhosis,with ultimate NAFLD associated Hepatocellular carcinoma(NAFLD-HCC). Enhanced corroborate illustrated that gut microbiome possess an essential part in initiating besides propagating NAFLD via via gut-liver axis .The gut-liver axis represents the reciprocal connection amongst gut as well as the liver constituted by the portal circulation, Bile Acids along with systemic circulation.This gut dysbiosis aids in the generation of NAFLD by resulting in dysregulation of gut-liver axis,causing an escalated Intestinal permeability besides uncontrolled microbial metabolites transportation in the liver. Hence here we conducted a Thus here we conducted a systematic review utilizing search engine pubmed,google scholar and others utilizing the MeSH terms like NAFLD; NASH; NAFLD-HCC; gut-liver axis; gut dysbiosis Intestinal permeability; Bile Acids circulation ; portal circulation probiotics.; prebiotics;FMT; individuals therapy treatment strategies, to update our earlier work from 2008 to 2022 till date.We found a total of 300 articles out of which we selected 103 articles for this update review.No meta-analysis was done.Thus we have described step by step the knowledge regarding gut microbiome dysbiosis alongwith metabolomic alterations. amongst steatosis NASH fibrosis alongwith NAFLD-HCC.Furthermore the different treatment strategies Inclusive of probiotics.; prebiotics;FMT; individuals therapy treatment strategies, are detailed besides escalating Akkermansia muciniphilia amounts.
... Zhou., et al. [4] observed that FMT might improve HFD -stimulated NASH by controlling GM, escalating SCFAs amounts, along with recovering the gut barrier by escalating butyrate and ZO expression. Despite comprehensive work till date no advocated drug is there for these diseases in particular for this greater robust NASH [5,6]. ...
Full-text available
Key mechanisms involved in the regulation of intestinal microbiota during NASH progression. Intestinal dysbiosis results in disruption of intestinal SCFAs, bile acids, and choline metabolic homeostasis, as well as increases LPS and endogenous alcohol production and NLPR3/6 activation, subsequently affecting the progression of ANSH. (A) SCFAs inhibit hepatic steatosis, inflammation, and protect the integrity of the intestinal barrier. Dysbiosis decreases SCFA production, thereby promoting the NASH process. (B) The metabolism of bile acids is regulated by FXR and TGR5. FXR signaling suppresses hepatic steatosis and insulin resistance, as well as negative feedback inhibits bile acid synthesis; TGR5 can protect the liver from inflammation and insulin resistance. However, dysbiosis will reduce the activity of FXR and TGR5 signaling. (C) Intestinal microbiota metabolizes choline to TMAO, but the effect of TMAO on NASH is controversial. (D) LPS mainly affects the progress of NASH through LPS-TLR4 and NF-κB signaling pathways, including hepatic inflammation, fibrosis and liver injury. (E) Activation of NLRP3 in the liver promotes liver damage, but NLRP3 in the intestine maintains intestinal homeostasis and improves intestinal dysbiosis. NLRP6 inhibits NASH progression by inhibiting TLR4/NF-κB signaling and TG accumulation and promoting AMP and IL-18 secretion. (F) Intestinal microbiota increases the production of endogenous alcohol and promotes the progress of NASH. SCFAs, short chain fatty acids; MCT1, monocarboxylate transporter 1; SMCT1, sodium‐coupled monocarboxylate transporter 1; AMPK, AMP activated protein kinase; PPARα, Peroxisome proliferator-activated receptor α; GPR41/43, G protein-coupled receptor 41/43; IL-18, Interleukin 18; PYY, peptide YY; GLP1, Glucagon like peptide 1; TLR4, Toll-like Receptor 4; Treg, regulatory T; FXR, Farnesol X receptor; LRH-1, liver receptor homolog 1; CYP7A1, cholesterol 7a hydroxylated enzyme; FGF15/19, fibroblast growth factors 15/19; FGFR4, fibroblast growth factor receptor 4; SREBP-1c, sterol regulatory element-binding protein 1c; TGR5, Takeda G protein-coupled receptor 5; GLP-1R, GLP-1 receptor; NF-κB, nuclear factor - kappaB, TMA, trimethylamine; TMAO, trimethylamine-N-oxide; FMO, flavin monooxygenases; LPS, lipopolysaccharide; LBP, LPS binding protein; TGF-β, transforming growth factor-β; BAMBI, bone morphogenetic protein and active membrane-bound inhibitor; AMPs, antimicrobial peptides; NLRP3/6, nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3/6; TAB2/3, TGF-β activated kinase 1 binding protein 2/3;
... In the last decade numerous hurdles have been tackled resulting in clinical generation of DNL hampering agents initiated for CVD, NASH, canceretc. We reviewed different modalities for obesity therapy besides that for NAFLD/NASH, [155][156][157][158][159][160][161][162][163][164][165][166] yet no drug has been approved for obesity/ NAFLD/NASHtherapy. Today when single cell evaluation of cellular metabolism is feasible a thrilling research aspect estimated if particular cell kinds having DNL upregulation in variable pathological situations is existent. ...
Full-text available
For survival fatty acids are necessary, working as substrates for bioenergy generation, structural constitutents along with signaling molecules. With their key part, evolutionary modes bycells for fatty acids formation from alternative carbon resources via a event labelled as de novo’’ lipogenesis ( DNL). In spite of the knowledge of significance regarding its up regulation abnormalities being correlatedwith numerous types of pathological conditions. Attempt at hampering core DNL enzymes inclusive ofcitrate/iso citratecarrier(CIC), ATP citrate lyase ( ACLY), acetyl CoA carboxylase(ACC) along with fatty acid synthase( FAS) apparently should turn out to be a good therapeutic approach. Although numeroushurdles anticipated regarding effectiveness, selectiveness besides safety variable newer classes of synthetic DNL hampering agents have reached clinical stage generation besides becoming the basis for a newer class of treatment substances. Having earlier reviewed numerous articles regarding obesity along with its co-morbidities type2 Diabetes mellitus (T2DM) NAFLD /NASH here we have presented a narrative review regarding the evolutionary generation of DNL hampering agents as potential treatment agents. For this we review utilizing search engine pubmed, google scholar; web of science; embase; Cochrane review library for which we have extracted data from earliest data with the recognition of significance of various enzymes besides their allosteric, covalent, transcriptional control of fatty acids generation & the problems encountered for their generation till date. Apart from obesity associated therapeutics their utility extends to acne vulgaris, various cancer thrapies besides treating neurod generational diseases. Keywords: de novo’’ lipogenesis ( DNL), FAS hampering agents, evolutionary generation
Conference Paper
Full-text available
upto 300 words) Type2 Diabetes mellitus(T2D) refers to a syndrome that by definition is secondary to numerous extents of βcells failure in addition to reduction in insulin sensitivity.Despite ,a lot of metabolic Impairment ,most patientsare classified as either presenting with T1D or T2D.Recently Ahlqvist etal.posited a new system of classification for adult onset disease ,keeping in view the heterogenic metabolic phenotypes of this disease.This new classification system might possess the potential for utilization for greater individualization of treatment depending on the underlying metabolic Impairments in this disease ,despite no existing mediation studies have developed data to validate this claim.Thus here we provide a brief introduction on the etiopathogenesis with regard to T2D as well as in patients acquiring Diabetes at adult age ,besides summarize the evolution of classification systems including one we had earlier provided. Subsequently we try to review the actions of various antidiabetic agents on insulin sensitivity along with β cell function in addition to the posited approaches for individualized therapy as per the various subgroups based on Ahlqvist etal's posit.Thus we conclude that the innovative T2D subgroups add to an intriguing model that could stimulate us to get better insight over the pathophysiology of this very wide group of T2D that aids in individualized treatment options on the basis of the underlying etiology of the disease.In these innovative T2D subgroups of adult onset disease that would aid in giving some antidiabetic agents that would prove be more advantageous for certain subgroups ,considering the major pathophysiology in addition to avoidance of endorgan injury .To start with it is just the initiation of trying to get in individualized therapy for T2D,along with studies that start performing evaluation of the current existence in addition to innovative drugs,prospectively in various subgroups possessing separate metabolic phenotypes to succeed in making therapy more individualized.
Full-text available
Worldwide, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest growing cancers. Epidemiological studies have not only shed light on the prevalence and incidence of the disease but have also unmasked important environmental risk factors, including the role of diabetes and dyslipidemia in disease pathogenesis. Genetic association studies have identified single nucleotide polymorphisms implicated in NAFLD-HCC, many of which are part of lipid metabolism pathways. Through these clinical studies and subsequently, translational and basic research, the role of statins as a chemoprotective agent has also emerged with ongoing clinical trials assessing their utility in HCC prevention and treatment. In this review, we summarize the recent epidemiological studies describing the burden of NAFLD-HCC in different patient populations and countries. We discuss the genetic and environmental risk factors for NAFLD-HCC and highlight the chemoprotective role of statins and aspirin. We also summarize what is known about NAFLD-HCC in the cirrhosis and non-cirrhosis populations and briefly address the role of surveillance in NAFLD-HCC patients.
Full-text available
Liver disease is the spectrum of liver damage ranging from simple steatosis called as nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). Clinically, NAFLD and type 2 diabetes coexist. Type 2 diabetes contributes to biological processes driving the severity of NAFLD, the primary cause for development of chronic liver diseases. In the last 20 years, the rate of non-viral NAFLD/NASH-derived HCC has been increasing rapidly. As there are currently no suitable drugs for treatment of NAFLD and NASH, a class of thiazolidinediones (TZDs) drugs for the treatment of type 2 diabetes is sometimes used to improve liver failure despite the risk of side effects. Therefore, diagnosis, prevention, and treatment of the development and progression of NAFLD and NASH are important issues. In this review, we will discuss the pathogenesis of NAFLD/NASH and NAFLD/NASH-derived HCC and the current promising pharmacological therapies of NAFLD/NASH. Further, we will provide insights into “adipose-derived adipokines” and “liver-derived hepatokines” as diagnostic and therapeutic targets from NAFLD to HCC.
Full-text available
The incidence of obesity is increasing in mammoth proportions so much so that associated comorbidity T2DM incidence is increasing markedly that we had to coin a term “Diabesity” to target both together. Earlier trying to review etiopathogenesis of both obesity and type 2 DM we found that whatever drugs that are formulated usually do not work with some complications and till now other than bariatric surgery we have no permanent cure for long term maintenance. Further T2DM might be a disease of 2 etiopathogenesis, namely inflammatory, as well as metabolic. Although metabolic inflammation has the properties of being systemic, their common initiating point is tissue resident macrophages, whose successful physiological or abnormal pathological adaptation to its microenvironment dictates disease course as well as severity. Earlier we reviewed macrophage polarization in case of nonalcoholic fatty liver disease (NAFLD). Here we review it more comprehensively regarding crucial modes, of macrophage polarization, inflammatory, as well as non inflammatory which sees to the formation of insulin resistance (IR) as well as type 2 diabetes mellitus (T2DM). Details of macrophage polarization, bioenergetics macrophage adaptations in different scenario is discussed in detail along with role of transcription factors like interferon regulatory factor 5 (IRF5), nuclear factor kappa B (NFKB), toll like receptor 4 (TLR4), liver X receptor (LXR), activator protein 1(AP1), hypoxia inducible factor 1(HIF1), signal transducers and activators of transcription (STATS) in all these signaling besides peroxisome proliferator activated receptor (PPAR).
Full-text available
Obesity is increasing at epidemic proportions both in children and adults posing a big public health problem among children as well as adults. With parallel increase in comorbidities like type2 diabetes mellitus (T2DM), metabolic syndrome (MetS) a need arises for developing medical therapies that can maintain long term weight loss. Earlier we have tried to consider multiple options like utilization of drug combinations like Qsymia, Contravene, Liraglutide, thylakoids, probiotics, Combination of glucagon like peptides1 (GLP1) with glucagon etc but nothing has proved to be as efficacious as BS in long term maintenance of weight loss. Earlier we had reviewed the cellular changes related to orexin A and B changes that are isoforms of neuropeptides that get liberated from the lateral hypothalamus (LH). Here we further review the pathophysiology of orexin neurons with regard to their role in neuroinflammation in the central nervous system (CNS) via microglial cell changes and role in spontaneous physical activity (SPA) and sleep physiology commonly termed sleep-wake promoting neuropeptides along with role in reward circuitry and how targeting them might be of help in treating obesity. Possibility is that subtle increases in SPA have been found to improve energy expenditure (EE) and that has been utilized in some workplaces where treadmill like chairs are utilized, restless people who keep sitting and standing do burn calories thus promoting carparks at distance places, no elevators have been thought as some ways by which lethargic individuals refuse to follow exercise might get helped by modulating orexin neurons besides correcting sleep problems coexisting with obesity
Full-text available
To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for treatment of nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Three large electronic databases were systematically searched (up to 15 December 2020) to identify placebo-controlled or active-controlled RCTs using different GLP-1 RAs. We included eleven placebo-controlled or active-controlled phase-2 RCTs (involving a total of 936 middle-aged individuals) that used liraglutide (n = 6 RCTs), exenatide (n = 3 RCTs), dulaglutide (n = 1 RCT) or semaglutide (n = 1 RCT) to specifically treat NAFLD or NASH, detected by liver biopsy (n = 2 RCTs) or imaging techniques (n = 9 RCTs). Compared to placebo or reference therapy, treatment with GLP-1 RAs for a median of 26 weeks was associated with significant reductions in the absolute percentage of liver fat content on magnetic resonance-based techniques (pooled weighted mean difference: −3.92%, 95% confidence intervals (CI) −6.27% to −1.56%) and serum liver enzyme levels, as well as with greater histological resolution of NASH without worsening of liver fibrosis (pooled random-effects odds ratio 4.06, 95% CI 2.52–6.55; for liraglutide and semaglutide only). In conclusion, treatment with GLP-1 RAs (mostly liraglutide and semaglutide) is a promising treatment option for NAFLD or NASH that warrants further investigation.
Full-text available
The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.
Full-text available
Background Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the associated cardiac dysfunction, i.e. heart failure with preserved ejection fraction (HFpEF). To overcome these limitations, we established a nutritional hamster model developing both NASH and HFpEF. We then evaluated the effects of the dual peroxisome proliferator activated receptor alpha/delta agonist elafibranor developed for the treatment of NASH patients. Methods Male Golden Syrian hamsters were fed for 10 to 20 weeks with a free choice diet, which presents hamsters with a choice between control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. Biochemistry, histology and echocardiography analysis were performed to characterize NASH and HFpEF. Once the model was validated, elafibranor was evaluated at 15 mg/kg/day orally QD for 5 weeks. Results Hamsters fed a free choice diet for up to 20 weeks developed NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18 immunostaining), bridging fibrosis, and a severe diastolic dysfunction with restrictive profile, but preserved ejection fraction. Elafibranor resolved NASH, with significant reduction in ballooning and fibrosis scores, and improved diastolic dysfunction with significant reduction in E/A and E/E' ratios. Conclusion Our data demonstrate that the free choice diet induced NASH hamster model replicates the human phenotype and will be useful for validating novel drug candidates for the treatment of NASH and associated HFpEF.
One quarter of the global population is estimated to have nonalcoholic fatty liver disease (NAFLD). The incidence of nonalcoholic steatohepatitis (NASH) is projected to increase by up to 56% in the next 10 years. NAFLD is already the fastest growing cause of hepatocellular carcinoma (HCC) in the USA, France and the UK. Globally, the prevalence of NAFLD-related HCC is likely to increase concomitantly with the growing obesity epidemic. The estimated annual incidence of HCC ranges from 0.5% to 2.6% among patients with NASH cirrhosis. The incidence of HCC among patients with non-cirrhotic NAFLD is lower, approximately 0.1 to 1.3 per 1,000 patient-years. Although the incidence of NAFLD-related HCC is lower than that of HCC of other aetiologies such as hepatitis C, more people have NAFLD than other liver diseases. Urgent measures that increase global awareness and tackle the metabolic risk factors are necessary to reduce the impending burden of NAFLD-related HCC. Emerging evidence indicates that reduced immune surveillance, increased gut inflammation and gut dysbiosis are potential key steps in tumorigenesis. In this Review, we discuss the global epidemiology, projections and risk factors for NAFLD-related HCC, and propose preventive strategies to tackle this growing problem.