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Carbohydrate intake and NAFLD: fructose as a weapon of mass destruction


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Abstract: Excessive accumulation of triglycerides (TG) in liver, in the absence of significant alcohol consumption is nonalcoholic fatty liver disease (NAFLD). NAFLD is a significant risk factor for developing cirrhosis and an independent predictor of cardiovascular disease. High fructose corn syrup (HFCS)- containing beverages were associated with metabolic abnormalities, and contributed to the development of NAFLD in human trials. Ingested carbohydrates are a major stimulus for hepatic de novo lipogenesis (DNL) and are more likely to directly contribute to NAFLD than dietary fat. Substrates used for the synthesis of newly made fatty acids by DNL are primarily glucose, fructose, and amino acids. Epidemiological studies linked HFCS consumption to the severity of fibrosis in patients with NAFLD. New animal studies provided additional evidence on the role of carbohydrate-induced de-novo lipogenesis and the gut microbiome in NAFLD. The excessive consumption of HFCS-55 increased endoplasmic reticulum stress, activated the stress-related kinase, caused mitochondrial dysfunction, and increased apoptotic activity in the liver. A link between dietary fructose intake, increased hepatic glucose transporter type-5 (Glut5) (fructose transporter) gene expression and hepatic lipid peroxidation, MyD88, TNF-α levels, gut-derived endotoxemia, toll-like receptor-4, and NAFLD was reported. The lipogenic and proinflammatory effects of fructose appear to be due to transient ATP depletion by its rapid phosphorylation within the cell and from its ability to raise intracellular and serum uric acid levels. However, large prospective studies that evaluated the relationship between fructose and NAFLD were not performed yet.
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The earliest stage of nonalcoholic fatty liver disease
(NAFLD) is hepatic steatosis, which is defined by hepatic
triglyceride concentration exceeding 55 mg/g liver (5.5%) (1).
NAFLD can progress to nonalcoholic steatohepatitis
(NASH), characterized by the signs of hepatocyte injury
and hepatic inflammation with collagen deposition.
Approximately 10-29% of patients with NASH will develop
cirrhosis within 10 years (2). NAFLD is an independent
and a stronger predictor of cardiovascular disease than
peripheral or visceral fat mass (3,4). NAFLD prevalence
is 15% in non-obese patients, but increases in obese [body
mass index (BMI) =30.0-39.9 kg/m2] and extremely obese
(BMI 40.0 kg/m2) patients to 65% and 85%, respectively (5).
In addition to genetic susceptibility, environmental
factors play important roles in the development of NAFLD
& NASH (6-8). The rapid rise in NAFLD prevalence
supports the role of environmental factors. It was reported
that overconsumption of high fructose corn syrup (HFCS)
in the soft-drink and pre-packaged foods were linked to
the rise in the prevalence of obesity and associated with
NAFLD. Ingested carbohydrates are a major stimulus
Review Article
Carbohydrate intake and NAFLD: fructose as a weapon of mass
Metin Basaranoglu1, Gokcen Basaranoglu2, Elisabetta Bugianesi3
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, 2Department of Anaesthesiology, Bezmialem Vakif University
Faculty Hospital, Istanbul, Turkey; 3Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Torino, Turin, Italy
Correspondence to: Metin Basaranoglu, MD, PhD. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Bezmialem Vakif
University Faculty Hospital, Istanbul, Turkey. Email:
Abstract: Excessive accumulation of triglycerides (TG) in liver, in the absence of significant alcohol
consumption is nonalcoholic fatty liver disease (NAFLD). NAFLD is a signicant risk factor for developing
cirrhosis and an independent predictor of cardiovascular disease. High fructose corn syrup (HFCS)-
containing beverages were associated with metabolic abnormalities, and contributed to the development of
NAFLD in human trials. Ingested carbohydrates are a major stimulus for hepatic de novo lipogenesis (DNL)
and are more likely to directly contribute to NAFLD than dietary fat. Substrates used for the synthesis of
newly made fatty acids by DNL are primarily glucose, fructose, and amino acids. Epidemiological studies
linked HFCS consumption to the severity of brosis in patients with NAFLD. New animal studies provided
additional evidence on the role of carbohydrate-induced de-novo lipogenesis and the gut microbiome in
NAFLD. The excessive consumption of HFCS-55 increased endoplasmic reticulum stress, activated the
stress-related kinase, caused mitochondrial dysfunction, and increased apoptotic activity in the liver. A link
between dietary fructose intake, increased hepatic glucose transporter type-5 (Glut5) (fructose transporter)
gene expression and hepatic lipid peroxidation, MyD88, TNF-α levels, gut-derived endotoxemia, toll-like
receptor-4, and NAFLD was reported. The lipogenic and proinflammatory effects of fructose appear to
be due to transient ATP depletion by its rapid phosphorylation within the cell and from its ability to raise
intracellular and serum uric acid levels. However, large prospective studies that evaluated the relationship
between fructose and NAFLD were not performed yet.
Keywords: Nonalcoholic fatty liver disease (NAFLD); high fructose corn syrup (HFCS); carbohydrate; de novo
lipogenesis (DNL)
Submitted Sep 19, 2014. Accepted for publication Oct 29, 2014.
doi: 10.3978/j.issn.2304-3881.2014.11.05
View this article at:
2Basaranoglu et al. HFCS and NAFLD
© Hepatobiliary Surgery and Nutrition. All rights reserved. Hepatobiliary Surg Nutr
for hepatic de novo lipogenesis (DNL), and more likely to
directly contribute to NAFLD than dietary fat intake.
Pathophysiology of NAFLD
Obesity is associated with low-grade chronic inammation (9).
This chronic inflammation is a link between obesity and
insulin resistance. Insülin resistance plays a central role in
NAFLD pathogenesis.
Normally, insulin binds α-subunits of its receptor on
adipocytes and hepatocytes leading to autophosphorylation
of β-subunits and activates tyrosine kinase (10). The
autophosphorylated receptor activates insulin receptor
substrate (IRS) -1, IRS-2, Src homology collagen (Shc), and
APS [adaptor protein with a pleckstrin homology (PH) and
Src homology 2 (SH2) domain] which activate downstream
components of the insulin signaling pathways. In both skeletal
muscle and adipose tissue, these insulin-mediated signaling
cascades induce the translocation of glucose transporters
(GLUT). IRS-1 was linked to glucose homeostasis while
IRS-2 was linked to the lipogenesis with the regulation of
lipogenic enzymes sterol regulatory element-binding protein-
1c (SREBP-1c) and fatty acid synthase.
In obese, increased production of TNF-α and
plasma free fatty acids are major stimuli of Ser 307
phosphorylation of IRS-1 (11). Inhibition of IRS-1 due to
the phosphorylation of its Ser 307 residues also requires
the activation of both c-Jun N-terminal kinase (JNK) and
inhibitor κB kinase β (IKK-β). Both TNF-α and free fatty
acids induce JNK and IKK-β activation. TNF-α stimulates
phosphorylation of Ser residues of both IRS-1 and IRS-2
in hepatocytes and Ser residues of IRS-1 in muscles. JNK
is one of the stress related kinases and plays an important
role in the development of insulin resistance. Activated
JNK induces Ser 307 phosphorylation of IRS-1, disturbs
insulin downstream signaling, and subsequently causes
insulin resistance. Protein kinase C theta (PKCθ) and
IKK-β are two pro-inammatory kinases involved in insulin
downstream signaling that are activated by lipid metabolites.
IKK-β phosphorylates the inhibitor of nuclear factor kappa
B (NF-κB). NF-κB has both apoptotic and anti-apoptotic
The hepatocyte mitochondria are the main site of
β-oxidation of free fatty acids (12-15). The electrons
removed from free fatty acids during β-oxidation, eventually
leading to ATP synthesis. Depletion of the energy (ATP)
stores increases the susceptibility of hepatocytes to various
Carbohydrates: glucose, fructose and HFCS
Fructose is a monosaccharide (16,17). It is a sweet tasting
sugar and found naturally in fruits and some vegetables.
Fructose is sweeter than either glucose or sucrose. Before
the development of the worldwide sugar industry, fructose
was limited in the human diet. Honey, dates, raisins,
molasses, and gs have a content of >10% of this sugar. A
fructose content of 5-10% by weight is found in grapes, raw
apples, apple juice, persimmons, and blueberries.
Today, the principal sources of fructose in the American
diet are HFCS (18-20). Industrially, HFCS are frequently
found in soft drinks and pre-packaged foods. The most
common form of HFCS is HFCS 55, which has 55%
fructose compared to sucrose which is 50% fructose. Foods
and drinks are made with HFCS 55. A study showed that
certain popular sodas and other beverages contain a fructose
content approaching 65% of sugars. Moreover, HFCS can
be made to have any proportion of fructose, as high as 90%.
It was recently reported that more than 50% of preschool
children consume some calorie-sweetened beverages.
Several meta-analyses suggested that the consumption
of sugar-sweetened beverages is related to the risk of
metabolic syndrome; increased triglycerides (TG) levels,
stimulated DNL and increased visceral fat (20,21) (Figure 1).
Another study compared milk, diet cola, a sugar-sweetened
cola, and water. The study showed that the sugar-sweetened
beverage increased liver and visceral fat over the 6 months
of beverage intake by consuming two 16-ounce sugar-
containing beverages per day for 6 months (22).
Fructose is an intermediary in the metabolism of
glucose (17-20). But, it differs in several ways from glucose.
Fructose is poorly absorbed from the gastrointestinal tract
by a different mechanism than that for glucose (Figure 2).
Most cells have only low amounts of the glucose transporter
type-5 (GLUT-5) transporter, which transports fructose
into cells. Glucose is transported into cells by GLUT-
4, an insulin-dependent transport system. Fructose is
almost entirely cleared by the liver. Hepatic metabolism
of fructose stimulates lipogenesis. These events are
independent of insulin exertion and phosphofructokinase
regulation step. High fructose intake is associated with
increased plasma TGs by an up-regulation of hepatic DNL
and TGs secretion, and a decreased clearance of very low
density lipoprotein triglyceride (VLDL-TG). Fructose
phosphorylation in the liver consumes ATP, consequently
the accumulated ADP serves as substrate for uric acid
formation. These events facilitate hepatic oxidative damage
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and lipid peroxidation.
Aeberli et al. conducted a 4-week randomized cross-over
study with a 4-week wash-out between each diet in nine
healthy young men comparing four different soft drinks
with levels of fructose, glucose, and sucrose that are closer
to normal intake (23). This is a randomized crossover
comparison of four beverages with two levels of fructose,
glucose, and sucrose (50% fructose). The investigators
examined insulin sensitivity of the liver and the whole body
by the hyperinsulinemic-euglycemic clamp technique. They
showed that compared with the high-glucose beverage, the
low-fructose beverage impaired hepatic insulin sensitivity,
but not whole-body insulin sensitivity. In addition, they
found that total and low density lipoprotein (LDL)
cholesterol levels were increased by fructose relative to
glucose. Free fatty acids were also increased in the fructose
beverage groups. This study adds to the information about
the role of fructose either from sucrose (ordinary table
sugar) or from high-fructose corn syrup in initiating liver
dysfunction and the metabolic syndrome.
Cohen and Schall also reported that sucrose increased TG
following a meal but glucose had no effects on lipids (24).
Fructose as a main source of hepatic DNL in NAFLD
Increased DNL (increased hepatocellular carbohydrate is
converted to fat) is a significant contributor to increased
hepatic triglyceride content in NAFLD (25,26). Recent
techniques such as isotope methodologies, multiple-
stable-isotope approach and gas chromatography/mass
spectrometry showed that relative contribution of three
fatty acid sources to the accumulated fat in NAFLD as
adipose tissue, DNL and dietary carbohydrates. Twenty-six
percentage of the liver fat arises from DNL and 15% from
the diet in patients with NAFLD.
Fructose can induce NAFLD by its ability to act as an
upregulated substrate for DNL and by bypassing the major
rate-limiting step of glycolysis at phosphofructokinase.
Continuous fructose ingestion may cause a metabolic
burden on the liver through the induction of fructokinase
and fatty acid synthase (27).
Evidence support fructose as a weapon of mass
destruction in NAFLD
Animal studies
Fructose ingestion can rapidly cause fatty liver in animals
with the development of leptin resistance (28-30). It was
reported that consumption of high-fructose meals reduced
24-hour plasma insulin and leptin concentrations, increased
postprandial fasting and not suppress circulating ghrelin
(Figure 3). Our group previously demonstrated that male
C57BL/6 mice fed relevant amounts of a high-fructose corn
Increased consumption of HFCS 55-90 in
soft drinks and pre-packaged foods
Metabolic syndrome
Stimulated de novo lipogenesis
Increased visceral fat
Figure 1 Increased consumption of sugar-sweetened beverages and
pre-packaged foods is related to the risk of metabolic syndrome.
High fructose corn syrup (HFCS) stimulates de novo lipogenesis
and finally development of nonalcoholic fatty liver disease
(NAFLD) & nonalcoholic steatohepatitis (NASH).
Figure 2 Fructose is poorly absorbed from the gastrointestinal
tract by the glucose transporter type-5 (GLUT-5) transporter.
Glucose is transported into cells by GLUT-4, an insulin-dependent
transport system. Fructose is almost entirely cleared by the liver (the
circulating concentration is 0.01 mmol/L in peripheral blood,
compared with 5.5 mmol/L for glucose). Hepatic metabolism of
fructose induces de novo lipogenesis. Fructose phosphorylation in
the liver consumes ATP, consequently the accumulated ADP serves
as substrate for uric acid formation.
Liver FAT
Adipose tissue FAT
(glucose & ınsülin)
4Basaranoglu et al. HFCS and NAFLD
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syrup equivalent (drinking water containing 55% fructose)
for 16 weeks developed severe hepatic steatosis associated
with necroinammatory changes (31).
Ackerman et al. showed that rats given fructose-enriched
diet increased hepatic TG and cholesterol amounts (32).
Fructose fed rodent at supraphysiological doses under
isocaloric (~60% energy) or hypercaloric (+30% excess
energy) conditions induces steatosis and steatohepatitis by
DNL; fructose accounts for 60-70% of fatty acids in this
study (33).
Nagai et al. demonstrated that the transcriptional
factor peroxisome proliferator-activated receptor gamma
coactivator-1 beta (PGC-1 β) plays a crucial role in the
pathogenesis of fructose-induced insulin resistance in Sprague-
Dawley rats (34). Armutcu et al. reported that male Wistar
albino rats provided with drinking water containing 10%
fructose for 10 d developed macrovesicular and microvesicular
steatosis without inammation in the liver (35).
Lipocalin-2 (LCN-2) is a 25-kDa secretory glycoprotein
initially identied in human neutrophils and it is abundantly
present in the circulation (36). It was demonstrated that
the liver is the main source of serum LCN-2 which plays
a key role in the acute-phase response, regulation of
immune responses, and apoptosis. A recently published
study investigated LCN-2 expression and its role in rat
models fed by high fructose (1). In this study, fatty liver
was triggered in male Sprague-Dawley rats fed either with
liquid Lieber-DeCarli (LDC) or LDC +70% cal fructose
(L-HFr) diet for 4 or 8 weeks. Both LDC-fed and L-HFr-
fed rat showed fatty liver, histologically. In the liver, the
transcription of inducible nitric oxide synthase (iNOS), and
TNF-α was significantly up-regulated at week 4. Hepatic
LCN-2 expression was 90-fold at week 4 and 507-fold at
week 8 higher in L-HFr-subjected ratsvs.control (P<0.001).
Additionally, fasting leptin and TG were elevated in the
L-HFr regimen. Moreover, protein expression of hepatic
LCN-2, CD14, phospho-MAPK, caspase-9, cytochrome-c
and 4-hydroxynonenal were increased in the L-HFr group.
The localization of LCN-2 was predominantly restricted
to MPO+ granulocytes in the liver. This study showed that
fructose diet up-regulates hepatic LCN-2 expression, which
correlates with the increased indicators of oxidative stress
and mitochondrial dysfunction. The level of fasting blood
uric acid was significantly elevated in L-HFr-treated rats.
Hepatic GLUT-5 (fructose transporter) gene expression
was also signicantly elevated in L-HFr fed rats, which was
correlated with the accumulated fat in the liver.
A very low-carbohydrate diet causes weight loss and
increased hepatic and myocardial fatty acid oxidation
in wild-type mice, compared with mice maintained on
standard chow diets rich in polysaccharides (37). A recent
study revealed that C57BL/6J mice over 12-week fed
with very low-carbohydrate, low-protein, and high-fat
ketogenic diet led to hepatic fat accumulation, systemic
glucose intolerance, hepatic endoplasmic reticulum stress,
steatosis, cellular injury, and macrophage accumulation (38).
However, animals remain lean and insulin-induced hepatic
Akt phosphorylation and whole-body insulin responsiveness
was not impaired. The ketogenic diets provoked weight loss
in rodents. However, long-term maintenance on a ketogenic
diet stimulated the development of NAFLD and systemic
glucose intolerance in mice (37,38).
Human studies
Small cross-sectional and retrospective case–control studies
showed an association between fructose-containing sugar
intake and NAFLD (39-41). A meta-analyses showed
a triglyceride-raising effect of fructose (39). A recently
published human study investigated whether there is a
relation between spontaneous carbohydrate intake and
NAFLD (41). They found that hepatic steatosis was
related to the energy and carbohydrate intakes. The role of
dietary carbohydrates was detectable in the range of usual
carbohydrate intake: 32% to 58% calories.
Increased HFCS
Plasma leptin
De novo lipogenesis
• Oxidation
insulin levels
Figure 3 Fructose ingestion can rapidly cause fatty liver in animals
by the development of leptin resistance, reduced plasma insulin
and leptin concentrations and not suppress circulating ghrelin.
HFCS, high fructose corn syrup; NAFLD, nonalcoholic fatty liver
disease; NASH, nonalcoholic steatohepatitis.
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A systematic review and meta-analysis of controlled
feeding trials investigated effect of fructose on markers
of NAFLD (42). They found seven isocaloric trials, in
which fructose was exchanged isocalorically for other
carbohydrates, and six hypercaloric trials, in which the
diet was supplemented with excess energy (+21-35%
energy) from high-dose fructose (+104-220 g/day).
Although there was no effect of fructose in isocaloric trials,
fructose in hypercaloric trials increased both hepatic lipid
[standardized mean differences (SMD) =0.45; 95% condence
interval (CI): 0.18-0.72] and alanine aminotransferase (ALT)
[mean difference (MD) =4.94 U/L; 95% CI: 0.03-9.85].
They concluded that isocaloric exchange of fructose for other
carbohydrates does not induce NAFLD. Fructose providing
excess energy and raises hepatic lipid amount and serum
ALT. Moreover, this study concluded that finding of a lack
of effect of fructose on NAFLD markers in isocaloric trials.
Energy represented an important confounding factor in the
effect of fructose in this meta-analysis. Main limitation of this
meta-analysis was that few trials were available for inclusion
and most of them were small and short (4 weeks).
Ryan et al. reported a post hoc analysis of 52 obese, insulin
resistant adults in a weight loss program (43). These patients
were randomized to receive either a low carbohydrate
diet (40% carbonhydrate/40% fat) or a low fat diet (60%
carbohydrate/25% fat) for 16 weeks. Both groups lost a
significant amount of weight over the trial period. Serum
ALT levels decreased twice in the low carbohydrate diet
compared to the low fat diet. Insulin resistance levels were
also shown to decrease in both groups with no significant
differences between them. The authors concluded that
low carbohydrate diets are more beneficial than low fat
diets at reducing ALT levels. de Luis et al. reported that a
3-month intervention of hypocaloric diet (either low fat or
low carbohydrate) in obese patients improved biochemical
parameters, BMI and circumference (44).
Rodríguez-Hernández et al. demonstrated effect of low
fat and low carbohydrate diet on liver transaminases (45).
This trial included 54 women, with ultrasonographically
diagnosed NAFLD, and randomly assigned them to either
a low fat (25% protein, 10% fat, 54% carbohydrate) or low
carbohydrate (27% protein, 28% fat, 45% carbohydrate)
diet for a period of 6 months. At the end of the trial, those
on the low carbohydrate diet lost 5.7% of their body weight
and those in the low fat group 5.5%, a non-significant
result. ALT and AST levels were decreased in both groups
without signicant difference.
In another study by Haufe et al. demonstrated in a total
of 102 patients including both male and female, over a
6-month period diet therapy with low carbohydrate (90 g
of carbohydrate and 0.8 g protein per kg weight, 30%
fat) and low fat (20% fat, 0.8 g of protein per kg, the
remainder carbohydrate) (46). This study results were also
similar to Rodríguez-Hernández et al. study results (45). In
addition, intrahepatic fat content also not showed statistical
difference, 47% decreased in the low carbohydrate group
and 42% decreased hepatic fat content in the low fat group.
Sevastianova et al. demonstrated 16 subjects (BMI
=30.6±1.2) for 3 weeks induced on high carbohydrate diet
(>1,000 Kcal) showed >10-fold greater relative change in
liver fat (27%) than in body weight (2%) and increased
liver fat positively correlated with DNL (47). Furthermore,
consequent hypocaloric diet for 6 months led to decrease
in body weight as well as reduced liver fat to normal. This
study suggests that human fatty liver accumulates fat during
carbohydrate overfeeding and support a role for DNL in
the pathogenesis of NAFLD.
Low-carbohydrate diets have been shown to promote
weight loss, decrease intrahepatic triglyceride content, and
improve metabolic parameters of patients with obesity (48).
A meta-analysis investigated the long-term (6 or more
months) effects of low-carbohydrate diets (45% of energy
from carbohydrates) versus low-fat diets (30% of energy
from fat) on metabolic risk factors by randomized controlled
trials (48). Totally 2,788 participants met the predetermined
eligibility criteria (from January 1, 1966 to June 20, 2011)
and were included in the analyses. Both low-carbohydrate
and low-fat diets lowered weight and improved metabolic
risk factors. Compared with participants on low-fat diets,
persons on low-carbohydrate diets experienced a slightly but
statistically signicantly lower reduction in total cholesterol,
and LDL cholesterol, but a greater increase in high density
lipoprotein cholesterol and a greater decrease in TG.
Abdelmalek et al. studied 341 adult NAFLD patients (49).
They evaluated whether increased fructose consumption
correlates merely with the development of NAFLD or
promote the transition from NAFLD to NASH and more
advanced stages of liver damage. Fructose consumption
was estimated based on reporting (frequency × amount) of
kool, fruit juices, and non-dietary soda intake, expressed
as servings per week. The authors found that increased
fructose consumption was univariately associated with
decreased age (P<0.0001), male gender (P<0.0001),
hypertriglyceridemia (P<0.04), low HDL cholesterol
(P<0.0001), decreased serum glucose (P<0.001), increased
calorie intake (P<0.0001) and hyperuricemia (P<0.0001).
6Basaranoglu et al. HFCS and NAFLD
© Hepatobiliary Surgery and Nutrition. All rights reserved. Hepatobiliary Surg Nutr
After controlling for age, gender, BMI, and total calorie
intake, daily fructose consumption was associated with lower
steatosis grade and higher brosis stage (P<0.05 for each).
In older adults (age >48 years), daily fructose consumption
was associated with increased hepatic inammation (P<0.05)
and hepatocyte ballooning (P=0.05). Abdelmalek et al.
concluded that daily fructose ingestion is associated with
reduced hepatic steatosis but increased brosis.
Aeberli et al. investigated the relation between fructose
ingestion and LDL particle size in children (50). They
showed that greater total and central adiposity are associated
with smaller LDL particle size and lower HDL cholesterol
in school-age children. Overweight children consume more
fructose from sweets and sweetened drinks than do normal-
weight children, and higher fructose intake predicts smaller
LDL particle size.
HFCS-containing beverages are associated with the
development of NAFLD by hepatic DNL. Epidemiological
studies linked HFCS consumption to the severity of
fibrosis in patients with NAFLD, too. Recently, animal
studies showed that excessive consumption of HFCS-55
increases hepatic Glut5 gene expression and TNF-alpha
levels, gut-derived endotoxemia, endoplasmic reticulum
stress, hepatic lipid peroxidation and apoptotic activity. The
lipogenic and proinammatory effects of fructose appear to
be due to transient ATP depletion. Fructose can also raise
intracellular and serum uric acid levels. Large prospective
studies that evaluated the relationship between fructose and
NAFLD are needed.
Key points
The rapid rise in NAFLD prevalence supports the role
of environmental factors.
Overconsumption of HFCS in the soft-drink is linked
to the rise in the prevalence of obesity and associated
with NAFLD.
Ingested carbohydrates are a major stimulus for
hepatic DNL, and more likely to directly contribute to
NAFLD than dietary fat intake.
Fructose phosphorylation in the liver consumes ATP,
consequently the accumulated ADP serves as substrate
for uric acid formation.
The lipogenic and proinammatory effects of fructose
appear to be due to transient ATP depletion.
This article is dedicated to the Tuscany and Aegean people,
the region of grape. All authors contributed equally during
the preparation of this manuscript.
Disclosure: The authors declare no conict of interest.
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Full-text available
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with an estimated prevalence of 25% globally. NAFLD is closely associated with metabolic syndrome, which are both becoming increasingly more common with increasing rates of insulin resistance, dyslipidemia, and hypertension. Although NAFLD is strongly associated with obesity, lean or nonobese NAFLD is a relatively new phenotype and occurs in patients without increased waist circumference and with or without visceral fat. Currently, there is limited literature comparing and illustrating the differences between lean/nonobese and obese NAFLD patients with regard to risk factors, pathophysiology, and clinical outcomes. In this review, we aim to define and further delineate different phenotypes of NAFLD and present a comprehensive review on the prevalence, incidence, risk factors, genetic predisposition, and pathophysiology. Furthermore, we discuss and compare the clinical outcomes, such as insulin resistance, dyslipidemia, hypertension, coronary artery disease, mortality, and progression to nonalcoholic steatohepatitis, among lean/nonobese and obese NAFLD patients. Finally, we summarize the most up to date current management of NAFLD, including lifestyle interventions, pharmacologic therapies, and surgical options.
Full-text available
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with a continuously growing prevalence. The pathophysiology of the disease is complex and includes several mechanisms, with metabolic syndrome and insulin resistance playing a major role. It is crucial to diagnose NAFLD before it advances to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis, presented by its complications which include ascites, portal hypertension, bleeding varices and encephalopathy. Another important complication of NAFLD and cirrhosis is hepatocellular carcinoma (HCC), a cancer with increasing incidence and poor prognosis. Even with the growing prevalence of NAFLD, diagnosis via liver biopsies is unrealistic, considering the costs and complications. Noninvasive tests, including serum biomarkers and elastography, are cost-effective and convenient, thereby replacing liver biopsies in diagnosing and excluding liver fibrosis. However, currently, these noninvasive tests have several limitations, such as variability, inadequate accuracy and risk factors for error. The limitations and variability of these tests comet the investigator to propose combining them in diagnostic algorithms to produce more accurate tools. Identifying patients with significant fibrosis is important for targeted therapies to prevent disease progression. Effective screening using noninvasive tests can be crucial for patient risk stratification and early diagnosis.
Nonalcoholic steatohepatitis (NASH) is one of the important liver diseases currently attracting attention in liver research and drug development. Appropriate mouse models should be used to identify the mechanisms underlying the pathogenesis and progression of NASH in humans and to evaluate the efficacy of anti-NASH agents under development to treat this disease. In this review, we first summarised recent histopathology and pathogenesis of NASH in humans, including the concept of resolution of inflammation. We also examined whether these characteristics of NASH in humans are adequately reflected in mouse models. Through this review, we identified the usefulness and limitations of mouse models widely used in research on NASH. Mouse models can be divided into three main types: diet models, chemical models using toxic compounds, and genetic models using genetically transgenic mice. Genotype models are likely suitable for evaluating anti-NASH compounds because fibrosis, which is considered an important index to determine the drug efficacy of NASH inhibitors, is rapidly induced in genetic models. Using these models, we introduced some selected cases of NASH inhibitor development. This review aims to enhance the understanding of the pathogenesis of NASH and provide a basis for successfully selecting and utilising appropriate animal models of NASH in the development of effective inhibitors.
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Nonalcoholic fatty liver disease (NAFLD) is a prevalent hepatic disease in the world. Disorders of branched chain amino acid (BCAA) metabolism is involved in various diseases. In this study, we aim to explore the role of BCAA metabolism in the development of NAFLD and the protective effect of BCATc Inhibitor 2, an inhibitor of cytosolic branched chain amino acid transaminase, against NAFLD as well as its underlying mechanism. It was found that oleic acid induced lipid accumulation and apoptosis in HepG2 and LO2 cells. Supplementation of BCAAs further aggravated oleic acid-induced lipid accumulation and apoptosis. In contrast, treatment of BCATc Inhibitor 2 ameliorated oleic acid-induced lipid accumulation and apoptosis. Molecularly, supplementation of BCAAs or treatment of BCATc Inhibitor 2 up-regulated or down-regulated the expression of SREBP1 and lipogenesis-related genes without affecting lipolysis-related genes. BCATc Inhibitor 2 maintained mitochondrial function by ameliorating oleic acid-induced mitochondrial ROS generation and mitochondrial membrane potential disruption. In addition, BCATc Inhibitor 2 treatment alleviated oleic acid-induced activation of JNK and AKT signaling pathway and Bcl2/Bax/Caspase axis. In conclusion, our results indicate BCAA metabolism is involved in NAFLD and BCATc Inhibitor 2 protects against oleic acid-induced lipid accumulation and apoptosis. These findings suggest that BCATc Inhibitor 2 is a promising candidate drug for the treatment of NAFLD.
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High sugar intake has long been recognized as a potential environmental risk factor for increased incidence of many non-communicable diseases, including obesity, cardiovascular disease, metabolic syndrome, and type 2 diabetes (T2D). Dietary sugars are mainly hexoses, including glucose, fructose, sucrose and High Fructose Corn Syrup (HFCS). These sugars are primarily absorbed in the gut as fructose and glucose. The consumption of high sugar beverages and processed foods has increased significantly over the past 30 years. Here, we summarize the effects of consuming high levels of dietary hexose on rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, inflammatory bowel disease (IBD) and low-grade chronic inflammation. Based on these reported findings, we emphasize that dietary sugars and mixed processed foods may be a key factor leading to the occurrence and aggravation of inflammation. We concluded that by revealing the roles that excessive intake of hexose has on the regulation of human inflammatory diseases are fundamental questions that need to be solved urgently. Moreover, close attention should also be paid to the combination of high glucose-mediated immune imbalance and tumor development, and strive to make substantial contributions to reverse tumor immune escape.
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Non-alcoholic fatty liver disease (NAFLD) and its progressive subtype non-alcoholic steatohepatitis (NASH) are the most prevalent liver diseases, often leading to hepatocellular carcinoma (HCC). This review aims to describe the present knowledge of the risk factors responsible for the development of NAFLD and NASH. I performed a literature review identifying studies focusing on the complex pathogenic pathway and risk factors of NAFLD and steatohepatitis. The relationship between NAFLD and metabolic syndrome is well established and widely recognized. Obesity, dyslipidemia, type 2 diabetes, hypertension, and insulin resistance are the most common risk factors associated with NAFLD. Among the components of metabolic syndrome, current evidence strongly suggests obesity and type 2 diabetes as risk factors of NASH and HCC. However, other elements, namely gender divergences, ethnicity, genetic factors, participation of innate immune system, oxidative stress, apoptotic pathways, and adipocytokines, take a leading role in the onset and promotion of NAFLD. Pathophysiological mechanisms that are responsible for NAFLD development and subsequent progression to NASH are insulin resistance and hyperinsulinemia, oxidative stress, hepatic stellate cell (HSC) activation, cytokine/adipokine signaling pathways, and genetic and environmental factors. Major pathophysiological findings of NAFLD are dysfunction of adipose tissue through the enhanced flow of free fatty acids (FFAs) and release of adipokines, and altered gut microbiome that generate proinflammatory signals and cause NASH progression. Understanding the pathophysiology and risk factors of NAFLD and NASH; this review could provide insight into the development of therapeutic strategies and useful diagnostic tools.
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Epidemiological studies have shown that excessive intake of fructose is largely responsible for the increasing incidence of non-alcoholic fatty liver, obesity, and diabetes. However, depending on the amount of fructose consumption from diet, the metabolic role of fructose is controversial. Recently, there have been increasing studies reporting that diets low in fructose expand the surface area of the gut and increase nutrient absorption in mouse model, which is widely used in fructose-related studies. However, excessive fructose consumption spills over from the small intestine into the liver for steatosis and increases the risk of colon cancer. Therefore, suitable animal models may be needed to study fructose-induced metabolic changes. Along with its use in global meat production, pig is well-known as a biomedical model with an advantage over murine and other animal models as it has similar nutrition and metabolism to human in anatomical and physiological aspects. Here, we review the characteristics and metabolism of fructose and summarize observations of fructose in pig reproduction, growth, and development as well as acting as a human biomedical model. This review highlights fructose metabolism from the intestine to the blood cycle and presents the critical role of fructose in pig, which could provide new strategies for curbing human metabolic diseases and promoting pig production.
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Background: The main composition of intestinal microbiota in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients has not yet been elucidated. In this, case-control study, we identified differences of intestinal microbiota in male patients with NAFLD, presumed NASH, and healthy controls. Materials and methods: We compared gut microbial composition of 25 patients with NAFLD, 13 patients with presumed NASH, and 12 healthy controls. Demographic information as well as clinical, nutritional, and physical activity data was gathered. Stool and blood samples were collected to perform the laboratory analysis. The taxonomic composition of gut microbiota was assessed using V4 regions of microbial small subunit ribosomal Ribonucleic acid genes sequencing of stool samples. Results: Firmicutes, Actinobacteria, and Bacteroidetes were the most frequently phyla in all groups. Our results revealed that Veillonella was the only genus with significantly different amounts in presumed NASH patients compared with patients with NAFLD (P = 2.76 × 10-6, q = 2.07 × 10-4, logFC = 5.52). Conclusion: This pilot study was the first study to compare gut microbial composition in patients with NAFLD and presumed NASH in the Middle East. Given the potential effects of gut microbiota on the management and prevention of NAFLD, larger, prospective studies are recommended to confirm this study's findings.
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Gut microbiota dysbiosis has been described in several metabolic disruptions, such as non-alcoholic fatty liver disease (NAFLD). Administration of resveratrol has been claimed to elicit benefits against NAFLD along with modulating gut microbiota composition. This investigation aims to study the putative mediating role of gut microbiota in the potential hepato-protective effects of resveratrol in a diet-induced NAFLD rat model. The involvement of bacteria from the Ruminococcaceae family in such effects was also addressed. Resveratrol administration resulted in lowered liver weight and serum total and non-HDL cholesterol concentrations, as well as in increased serum HDL cholesterol levels. The administration of this polyphenol also prevented obesogenic diet-induced serum transaminase increases. In addition, histopathological analysis revealed that resveratrol administration ameliorated the dietary-induced liver steatosis and hepatic inflammation. Gut microbiota sequencing showed an inverse relationship between some bacteria from the Ruminococcaceae family and the screened hepatic markers, whereas in other cases the opposite relationship was also found. Interestingly, an interaction was found between UBA-1819 abundance and resveratrol induced liver weight decrease, suggesting that for this marker resveratrol induced effects were greater when the abundance of this bacteria was high, while no actions were found when UBA-1819 abundance was low.
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Extracellular vesicles (EVs), defined as intercellular messengers that carry their cargos between cells, are involved in several physiological and pathological processes. These small membranous vesicles are released by most cells and contain biological molecules, including nucleic acids, proteins and lipids, which can modulate signaling pathways of nearby or distant recipient cells. Exosomes, one the most characterized classes of EVs, include, among others, microRNAs (miRNAs), small non-coding RNAs able to regulate the expression of several genes at post-transcriptional level. In cancer, exosomal miRNAs have been shown to influence tumor behavior and reshape tumor microenvironment. Furthermore, their possible involvement in drug resistance mechanisms has become evident in recent years. Hepatocellular carcinoma (HCC) is the major type of liver cancer, accounting for 75-85% of all liver tumors. Although the improvement in HCC treatment approaches, low therapeutic efficacy in patients with intermediate-advanced HCC is mainly related to the development of tumor metastases, high risk of recurrence and drug resistance. Exosomes have been shown to be involved in pathogenesis and progression of HCC, as well as in drug resistance, by regulating processes such as cell proliferation, epithelial-mesenchymal transition and immune response. Herein, we summarize the current knowledge about the involvement of exosomal miRNAs in HCC therapy, highlighting their role as modulators of therapeutic response, particularly chemotherapy and immunotherapy, as well as possible therapeutic tools.
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We investigated long-term effects of low carbohydrate diets on wild type mice, streptozotocin-injected and KKAy obese diabetic mice. These mice were pair-fed three different types of diets, standard chow (SC, C∶P∶F = 63∶15∶22), a low carbohydrate (LC, C∶P∶F = 38∶25∶37) diet and a severely carbohydrate restricted (SR, C∶P∶F = 18∶45∶37) diet for 16 weeks. Despite comparable body weights and serum lipid profiles, wild type and diabetic mice fed the low carbohydrate diets exhibited lower insulin sensitivity and this reduction was dependent on the amount of carbohydrate in the diet. When serum fatty acid compositions were investigated, monounsaturation capacity, i.e. C16:1/C16:0 and C18:1/C18:0, was impaired in all murine models fed the low carbohydrate diets, consistent with the decreased expression of hepatic stearoyl-CoA desaturase-1 (SCD1). Interestingly, both the hepatic expressions and serum levels of fibroblast growth factor 21 (FGF21), which might be related to longevity, were markedly decreased in both wild type and KKAy mice fed the SR diet. Taking into consideration that fat compositions did not differ between the LC and SR diets, we conclude that low carbohydrate diets have deleterious metabolic effects in both wild type and diabetic mice, which may explain the association between diets relatively low in carbohydrate and the elevated risk of cardiovascular events observed in clinical studies.
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Background & aims: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, no systemic studies from the United States have examined temporal trends, HCC surveillance practices, and outcomes of NAFLD-related HCC. Methods: We identified a national cohort of 1500 patients who developed HCC from 2005 through 2010 from Veterans Administration (VA) hospitals. We reviewed patients' full VA medical records; NAFLD was diagnosed based on histologic evidence for, or the presence of, the metabolic syndrome in the absence of hepatitis C virus (HCV) infection, hepatitis B, or alcoholic liver disease. We compared annual prevalence values for the main risk factors (NAFLD, alcohol abuse, and HCV), as well a HCC surveillance and outcomes, among HCC patients. Results: NAFLD was the underlying risk factor for HCC in 120 patients (8.0%); the annual proportion of NAFLD-related HCC remained relatively stable (7.5%-12.0%). In contrast, the proportion of HCC cases associated with HCV increased from 61.0% in 2005 (95% confidence interval, 53.1%-68.9%) to 74.9% in 2010 (95% confidence interval, 69.0%-80.7%). The proportion of HCC cases associated with only alcohol abuse decreased from 21.9% in 2005 to 15.7% in 2010, and the annual proportion of HCC cases associated with hepatitis B remained relatively stable (1.4%-3.5%). A significantly lower proportion of patients with NAFLD-related HCC had cirrhosis (58.3%) compared with patients with alcohol- or HCV-related HCC (72.4% and 85.6%, respectively; P < .05). A significantly higher percentage of patients with NAFLD-related HCC did not receive HCC surveillance in the 3 years before their HCC diagnosis, compared with patients with alcohol- or HCV-associated HCC. A lower proportion of patients with NAFLD-related HCC received HCC-specific treatment (61.5%) than patients with HCV-related HCC (77.5%; P < .01). However, the 1-year survival rate did not differ among patients with HCC related to different risk factors. Conclusions: NAFLD is the third most common risk factor for HCC in the VA population. The proportion of NAFLD-related HCC was relatively stable from 2005 through 2010. Although patients with NAFLD-related HCC received less HCC surveillance and treatment, a similar proportion survive for 1 year, compared with patients with alcohol-related or HCV-related HCC.
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Background: Concerns have been raised about the concurrent temporal trend between simple sugar intakes, especially of fructose or high-fructose corn syrup (HFCS), and rates of nonalcoholic fatty liver disease (NAFLD) in the United States. Objective: We examined the effect of different amounts and forms of dietary fructose on the incidence or prevalence of NAFLD and indexes of liver health in humans. Design: We conducted a systematic review of English-language, human studies of any design in children and adults with low to no alcohol intake and that reported at least one predetermined measure of liver health. The strength of the evidence was evaluated by considering risk of bias, consistency, directness, and precision. Results: Six observational studies and 21 intervention studies met the inclusion criteria. The overall strength of evidence for observational studies was rated insufficient because of high risk of biases and inconsistent study findings. Of 21 intervention studies, 19 studies were in adults without NAFLD (predominantly healthy, young men) and 1 study each in adults or children with NAFLD. We found a low level of evidence that a hypercaloric fructose diet (supplemented by pure fructose) increases liver fat and aspartate aminotransferase (AST) concentrations in healthy men compared with the consumption of a weight-maintenance diet. In addition, there was a low level of evidence that hypercaloric fructose and glucose diets have similar effects on liver fat and liver enzymes in healthy adults. There was insufficient evidence to draw a conclusion for effects of HFCS or sucrose on NAFLD. Conclusions: On the basis of indirect comparisons across study findings, the apparent association between indexes of liver health (ie, liver fat, hepatic de novo lipogenesis, alanine aminotransferase, AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake. Overall, the available evidence is not sufficiently robust to draw conclusions regarding effects of fructose, HFCS, or sucrose consumption on NAFLD.
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Obesity is associated with an activated macrophage phenotype in multiple tissues that contributes to tissue inflammation and metabolic disease. To evaluate the mechanisms by which obesity potentiates myeloid activation, we evaluated the hypothesis that obesity activates myeloid cell production from bone marrow progenitors to potentiate inflammatory responses in metabolic tissues. High fat diet-induced obesity generated both quantitative increases in myeloid progenitors as well as a potentiation of inflammation in macrophages derived from these progenitors. In vivo, hematopoietic stem cells from obese mice demonstrated the sustained capacity to preferentially generate inflammatory CD11c+ adipose tissue macrophages after serial bone marrow transplantation. We identified that hematopoietic MyD88 was important for the accumulation of CD11c+ adipose tissue macrophage accumulation by regulating the generation of myeloid progenitors from HSCs. These findings demonstrate that obesity and metabolic signals potentiate leukocyte production and that dietary priming of hematopoietic progenitors contributes to adipose tissue inflammation.
BACKGROUND: Earlier studies have suggested that infant feeding may program long-term changes in cholesterol metabolism. OBJECTIVE: We aimed to examine whether breastfeeding is associated with lower ...
Unlabelled: Plasma aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are usually increased in patients with nonalcoholic fatty liver disease (NAFLD). However, the factors behind their elevation remain unclear. The aim of this study was to assess the role of insulin resistance (IR) and liver triglyceride content in relation to histology in patients with NAFLD/nonalcoholic steatohepatitis (NASH) with normal or elevated ALT levels. To this end, we enrolled 440 patients, divided into three groups: no NAFLD (n = 60); NAFLD with normal ALT (n = 165); and NAFLD with elevated ALT (n = 215). We measured: (1) liver fat by proton magnetic resonance spectroscopy ((1)H-MRS); (2) severity of liver disease by biopsy (n = 293); and (3) insulin sensitivity in liver, muscle, and adipose tissue by a euglycemic hyperinsulinemic clamp with 3-(3)H-glucose. Patients with NAFLD and elevated ALT, even when well matched for body mass index to those with normal ALT, had worse adipose tissue insulin resistance (ATIR; P < 0.0001), higher liver triglyceride content (P < 0.0001), and lower plasma adiponectin (P < 0.05), but no differences in hepatic insulin resistance. Similar results were found when only patients with NASH were compared: both ATIR (P < 0.0001) and liver triglyceride content by (1)H-MRS (P < 0.0001) were worse in NASH with elevated ALT. Consistent with the (1)H-MRS data, steatosis on liver biopsy was also significantly increased in patients with NASH and elevated ALT levels (P < 0.0001). However, and most important, there were no differences in inflammation (P = 0.62), ballooning (P = 0.13), or fibrosis (P = 0.12). Conclusion: In patients with NAFLD or NASH, ATIR (but not HIR) and liver triglyceride content are major factors in the elevation of plasma aminotransferase levels. Patients with normal versus elevated ALT had similar severity of NASH, suggesting that plasma aminotransferase levels are misleading parameters for guiding clinical management.
Introduction: Fat accumulation in the liver is associated with metabolic syndrome; and through NASH, it could progress to hepatic cirrhosis and carcinoma. Since lipocalin-2 (LCN2) synthesis in the liver is influenced by inflammatory and metabolic processes, we aimed to examine LCN2 expression in two rat models of diet-induced fatty liver. Methods: Fatty liver was induced in male Sprague Dawley rats fed either with liquid Lieber-DeCarli (LDC) diet or LDC + 70% kcal fructose (L-HFr) for 4 and 8 weeks. Chow-fed animals served as controls. Immunohistochemistry on liver tissue was performed to study inflammation, fat degeneration, and the localization of LCN2 protein. LCN2 was assessed in liver and serum at mRNA and protein levels using RT-PCR, Western blot, and ELISA, respectively. Hepatic mRNA expression for inflammatory mediators (α2-macroglobulin (α2-m), mcp-1, ccr2, tnf-a, and il-8) were determined. Furthermore, CD14 protein levels in liver and serum were studied as well as ERK1/2 via Western blots. Fasting plasma triglycerides (TGs) levels were investigated. Results: LDC-treated and L-HFr-treated rats developed hepatic fat deposit accompanied with moderate inflammation, featuring a fatty liver. Contrary to chow or LDC diet, L-HFr regimen revealed significantly up-regulated hepatic LCN2 mRNA confirmed by the enhanced hepatic and serum LCN2 protein (P<0.001). LCN2 expression was detected mainly in ED1+macrophages and MPO+granulocytes predominantly in the liver of fructose-ingested animals. Ballooned hepatocytes didn't conserve LCN2 positivity during fixation step. Despite of significant increased mRNA levels of hepatic mcp1, ccr2, tnf-alpha, il-8, and α2-mc in L-HFr group; the increase of LCN2 was the most pronounced. Additionally, the expression of CD14, phosphERK1/2, and TGs levels were substantially higher in rats fed with L-HFr than LDC or control group. Conclusion: The present study suggests LCN2 as a biomarker for fructose-induced fatty liver.
Unlabelled: Nonalcoholic fatty liver disease (NAFLD), the accumulation of lipid within hepatocytes, is increasing in prevalence. Increasing fructose consumption correlates with this increased prevalence, and rodent studies directly support fructose leading to NAFLD. The mechanisms of NAFLD and in particular fructose-induced lipid accumulation remain unclear, although there is evidence for a role for endoplasmic reticulum (ER) stress and oxidative stress. We have evidence that NAFLD models demonstrate activation of the target of rapamycin complex 1 (Torc1) pathway. We set out to assess the contribution of ER stress, oxidative stress, and Torc1 up-regulation in the development of steatohepatitis in fructose-treated larval zebrafish. Zebrafish were treated with fructose or glucose as a calorie-matched control. We also treated larvae with rapamycin, tunicamycin (ER stress), or valinomycin (oxidative stress). Fish were stained with oil red O to assess hepatic lipid accumulation, and we also performed quantitative polymerase chain reaction (qPCR)and western blot analysis. We performed immunostaining on samples from patients with NAFLD and nonalcoholic steatohepatitis (NASH). Treatment with fructose induced hepatic lipid accumulation, mitochondrial abnormalities, and ER defects. In addition, fructose-treated fish showed activation of inflammatory and lipogenic genes. Treatment with tunicamycin or valinomycin also induced hepatic lipid accumulation. Expression microarray studies of zebrafish NAFLD models showed an elevation of genes downstream of Torc1 signaling. Rapamycin treatment of fructose-treated fish prevented development of hepatic steatosis, as did treatment of tunicamycin- or valinomycin-treated fish. Examination of liver samples from patients with hepatic steatosis demonstrated activation of Torc1 signaling. Conclusion: Fructose treatment of larval zebrafish induces hepatic lipid accumulation, inflammation, and oxidative stress. Our results indicate that Torc1 activation is required for hepatic lipid accumulation across models of NAFLD, and in patients.
Background: Studies of the GLP-1 receptor (GLP-1 R) have been directed at identifying polymorphisms in the GLP-1 R gene that may be a contributing factor in the pathogenesis of obesity and cardiovascular risk factors. Nevertheless, the role of GLP-1 R variants on body weight response after dietary intervention has not been evaluated. Objective: We decided to analyze the effects of the rs6923761 GLP-1 R polymorphism on body weight changes and metabolic parameters after 3 months of a hypocaloric diet. Design: A sample of 91 obese subjects was analyzed in a prospective way. The hypocaloric diet had 1,520 calories per day; 52 % of carbohydrates, 25 % of lipids and 23 % of proteins. Distribution of fats was: 50.7 % of monounsaturated fats, 38.5 % of saturated fats and 11.8 % of polyunsaturated fats. Results: In both genotype groups (GG vs. GA + AA), weight, body mass index, fat mass, waist circumference, systolic blood pressure, total cholesterol, LDL cholesterol, leptin, insulin and HOMA levels decreased. No statistical differences were detected in these changes between genotypes. In wild group (GG genotype) (pretreatment and posttreatment), BMI, weight, fat mass, waist circumference and triglyceride levels were higher than (GA + AA) group. Conclusion: Our data showed better anthropometric parameters and triglyceride levels in obese subjects with the mutant allele (A) of rs6923761 GLP-1R polymorphism. A lack of association of this polymorphism with weight loss or biochemical changes after a hypocaloric diet was observed.