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Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
https://ojs.bilpublishing.com/index.php/jer/index
Journal of Endocrinology Research
*Corresponding Author:
Kulvinder Kochar Kaur,
Kaur Centre For Human Reproduction, 721, G.T.B. Nagar, Jalandhar, Punjab, 144001, India;
Email: kulvinder.dr@gmail.com
DOI: https://doi.org/10.30564/jer.v3i2.3520
ARTICLE
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 INFO 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 signicant 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.
Keywords:
T2DM
Obesity
NAFLD
NASH
HCC
Adipokines
Hepatokines
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Journal of Endocrinology Research | Volume 03 | Issue 02 | July 2021
Distributed under creative commons license 4.0 DOI: https://doi.org/10.30564/jer.v3i2.3520
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, inuencing 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 signicant association
of NAFLD with T2DM along with obesity [37]. NAFLD
participates signicantly 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, inammation, 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.
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rhosis as well as HCC. No FDA approved drugs exist till
date.
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;
elabranor 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
done.
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 specic 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-
nicantly 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 signicantly 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 inammation, correlated with gut ob-
tained endotoxins, Oxidative stress (OS) as well as mito-
chondrial impair. It is intricately associated with NAFLD-
NASH.
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-
DOI: https://doi.org/10.30564/jer.v3i2.3520
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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 proinammatory
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 inamma-
tory propagation [59]. Once LBP deletion occurs it ame-
liorates inammation modulated liver damage [60]. TLR4
possesses the characteristics of stimulation of nuclear fac-
tor κB (NFκB) in addition to liberation of proinammato-
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).
DOI: https://doi.org/10.30564/jer.v3i2.3520
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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
inammation 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
signicant 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 inammation 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, inamma-
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 inltration [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
NASH
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 inuence 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 prole along with liver histology correlated ef-
fectiveness of these attractive drugs [19,20,81].
Pioglitazone
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 signicant benet 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].
DOI: https://doi.org/10.30564/jer.v3i2.3520
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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 inammation, 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
NASH.
DOI: https://doi.org/10.30564/jer.v3i2.3520
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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, inammation 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-
nicant 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, inammation
as well as lipoprotein constituents in addition to bile acid
generation [95]. In rodent models OCA has anti-inamma-
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 inammation 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 signicant 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 -β -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 inammatory 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 efciency, however it possesses safety
issues [108].
Elabranor, 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
proinammatory (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
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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 inuences
liver fat metabolism by causing reduction in FA genera-
tion along with escalation of β -oxidation [117]. Furthermore
it results in stimulation of cholesterol efux 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 decient (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
disulde (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 signicant 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 sufcient [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 rectied 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 inammation, apoptosis in addition to
brosis [133]. In murine models of NASH, it signicantly
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 inammation, 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 inuence 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-
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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 veried 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, inammation along with
fibrosis [140]. Hepatic Stellate cells (HSCs) on activation,
aid in brosis, liberate CCL5. CCL5 inuences probrotic
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 inammation like IL-1β, IL-6 as well as inu-
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 –
Adipocytokines
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 signicant therapeutic targets as well as
biomarkers in NAFLD robustness anticipation (Figure 5).
These adipocytokines might further have a signicant role
in generation of HCC.
Adiponectin
Adiponectin is a signicant 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 inammation. Pioglitazone, the antidiabetc which had
a benecial action on liver histology escalated adiponec-
tin amounts, in patients withNASH [93]. Nevertheless,
metformin the commonest used antidiabetc agent did not
have any signicant 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 efcacy
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 inammation,
anti brotic as well as anti apoptosis action [154]. Adiponec-
tin delivery escalates hepatic steatosis along with inam-
mation [154]. Moreover adiponectin expression has an in-
verse association with tumor size as well as recurrence [155].
Leptin
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
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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, inammation along with brosis [160]. Leptin ex-
pression has a positive association with cell proliferation
in HCC, as validated by proliferation marker Ki67 [133].
Resistin
Resistin is a proinammatory 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, inammation 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
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 signicant 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, inammation, 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 classied into anti-inammatory adipokines and pro-inammatory adipokines. Anti-inammatory adipokines
including adiponectin, irisin, and ghrelin inhibit the development and progression of NAFLD and NASH, whereas pro-inammatory
adipokines including leptin, resistin, and visfatin promote the development and progression of NAFLD and NASH.
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Irisin
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
Visfatin represents an inammatory 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 inammatory parameters have a
signicant 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 signicantly 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
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
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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
nonesteried 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 signicant 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 inammatory signaling pathways. Additionally, ANGPTL4 and 8
tend to function in opposite ways in HCC tumorigenesis.
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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. Signicantly 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 signicantly escalated, that causes dysfunction
of FXR as well as FGFR4 modulated signaling [218]. In cas-
es of NASH, FAF analogue signicantly 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 inammatory 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)
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)
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action along with TG uptake [168,229] [reviewed by us in
169]. Serum ANGPTL8 are signicantly 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 signicance 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 signicant 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 classication as per the etiology of NAFLD. It would
yield a signicant 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
perspective.
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DOI: https://doi.org/10.30564/jer.v3i2.3520
