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

Abstract

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.

Full text

© Hepatobiliary Surgery and Nutrition. All rights reserved. Hepatobiliary Surg Nutr 2014www.thehbsn.org
Introduction
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
destruction
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: metin_basaranoglu@yahoo.com.
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: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.11.05

2Basaranoglu et al. HFCS and NAFLD
© Hepatobiliary Surgery and Nutrition. All rights reserved. Hepatobiliary Surg Nutr 2014www.thehbsn.org
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
effects.
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
injuries.
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

3
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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
NAFLD & NASH
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.
Glucose
Fructose
Liver FAT
(fructose)
Adipose tissue FAT
(glucose & ınsülin)
Glucose
GLUT4
Fructose
GLUT5

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
consumption
Plasma leptin
levels
• De novo lipogenesis
• Oxidation
NAFLD & NASH
Circulating
ghrelin
Plasma
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.

5
HepatoBiliary Surgery and Nutrition, 2014
© Hepatobiliary Surgery and Nutrition. All rights reserved. Hepatobiliary Surg Nutr 2014www.thehbsn.org
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
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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.
Conclusions
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.
Acknowledgements
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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E. Carbohydrate intake and NAFLD: Fructose as a weapon of
mass destruction . Hepatobiliary Surg Nutr 2014. doi: 10.3978/
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