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J Hepatol. Author manuscript; available in PMC 2018 May 01.
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Published in final edited form as:

J Hepatol. 2018 May ; 68(5): 1063–1075. doi:10.1016/j.jhep.2018.01.019.
Fructose and Sugar: A Major Mediator of Nonalcoholic Fatty

Liver Disease
Thomas Jensen1, Manal F. Abdelmalek2, Shelby Sullivan1, Kristen J. Nadeau3, Melanie
Green3, Carlos Roncal1, Takahiko Nakagawa4, Masanari Kuwabara1, Yuka Sato1, Duk-Hee
Kang5, Dean R. Tolan6, Laura G Sanchez-Lozada7, Hugo R. Rosen1, Miguel A. Lanaspa1,
Anna Mae Diehl2, and Richard J Johnson1
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1Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado

2Duke University, Durham, North Carolina
3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
4Division of Future Basic Medicine, Nara Medical University, Nara, Japan
5Divisionof Nephrology, Department of Internal Medicine, Ewha Womans University College of
Medicine, Seoul, Korea
6Dept of Biology, Boston University, Boston, MA
7Laboratory of Renal Physiopathology, INC Ignacio Chávez, Mexico City
Abstract
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Nonalcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of metabolic syndrome,
and its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result
from overnutrition and sedentary lifestyle, recent evidence suggests that diets high in sugar (from
sucrose and/or high fructose corn syrup (HFCS)) not only increases the risk for NAFLD, but also,
nonalcoholic steatohepatitis (NASH). Here we review the experimental and clinical evidence that
fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired
fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked with
metabolism of fructose by fructokinase C, resulting in ATP consumption, nucleotide turnover and
uric acid generation that mediate fat accumulation. Alterations in gut permeability, microbiome,
Address all correspondence to: Thomas Jensen, M.D., Department of Endocrinology, University of Colorado, Denver, 1635 Aurora
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Court Mail Stop F732, Aurora, CO 80045, Phone: 720.848-2650, Fax: 720.848.2652, Thomas.Jensen@ucdenver.edu.
Authors’ Contributions: TJ and RJJ provided the main work of reviewing literature, formatting, the paper, and creation of table/figures
along with editing the paper. MFA, SS, KJN, MG, AMD, CR, DHK, TN, LGS, MK, YS, HRR, and LGS-L all provided editorial
feedback on the paper for additions and grammatical corrections.
Authors’ Disclosures: RJJ and ML discloses they are inventors on patents related to blocking fructose metabolism as a means to
reduce sugar craving and metabolic syndrome. RJJ, LGL, DRT, and ML also have equity in Colorado Research Partners LLC, which is
a startup company interested in developing novel fructokinase inhibitors. Dr Johnson has also received honoraria from Danone, Astra
Zeneca and is on the Scientific Board of Kibow, Inc. RJJ, ML and TJ have submitted a patent for V1b antagonists for the treatment of
IR and fatty liver disease. LGS-L receives research support from Danone Research and Kibow Biotech, Inc. MK, MG, CR, YS, KJN,
DHK SS, KJN, MFA, AMD, HRR do not have any relevant disclosures.
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Jensen et al. Page 2
and associated endotoxemia contributes to the risk of NAFLD and NASH. Early clinical studies
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suggest that reducing sugary beverages and total fructose intake, especially from added sugars,
may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more
definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation,
may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease.
Keywords
hepatic steatosis; hepatic inflammation; insulin resistance; sugar consumption; uric acid
“Apicius made the discovery, that we may employ the same artificial method of
increasing the size of the liver of the sow, as of that of the goose; it consists in
cramming them with dried figs, and when they are fat enough, they are drenched
with wine mixed with honey, and immediately killed.”
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Pliny the Elder (The Natural History 1ST Century AD,

eds John Bostock, Thomas Henry Riley)
Fructose is a simple sugar that is present in fruit and honey, but is also a major component in
the two most commonly used sweeteners, sucrose (table sugar, a disaccharide of fructose
and glucose), and high fructose corn syrup (HFCS, a mixture of fructose and glucose
monosaccharides). Intake of fructose has increased markedly over the last several hundred
years in parallel with the rise in intake of sucrose and HFCS, and currently the intake of
added sugars approaches 15 percent of overall energy intake in the average western diet,
with higher intakes among younger individuals (adolescents and adults in their twenties) and
among ethnic minorities (African American, Hispanic, Native American, and Pacific
Islanders) (1–4).
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The association of fructose with fatty liver dates back to Pliny the Elder who noted that the
famous Roman chef, Marcus Apicius, would make fatty liver (foie gras) by feeding geese
dates (a rich source of fructose). Later the German chemist, Justus von Liebig, made the
observation that simple carbohydrates stimulated fat accumulation in the liver. Indeed, by the
1960s numerous scientists reported that fructose was distinct from glucose in its unique
ability to increase both plasma triglycerides and liver fat (5–7). Metabolic studies in which
fructose was labeled further showed a 2 to 3-fold greater labeling of plasma and liver
triglycerides than that observed with glucose (8). However, overall the amount of fructose
being converted to triglycerides was relatively small (1 to 3% of the fructose), and did not
account for the lipogenic response observed (9, 10). This led some scientists to question the
importance of fructose as a means for stimulating lipid synthesis and accumulation.
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However, the importance of fructose reemerged with a report in this journal linking intake of
sugary sweetened beverages, and in particular fructose, with non-alcoholic fatty liver disease
(NAFLD) (11), an association that has been confirmed in numerous other studies and is now
a major area of research (12–15). Here we provide an update on the association and potential
mechanisms by which fructose causes fatty liver. One of the key findings is that it is not the
fructose molecule itself that is primarily responsible for making triglycerides, but rather fat
accumulates in the liver by the general activation of lipogenesis while at the same time

blocking fatty acid oxidation (16, 17). Indeed, the weight of studies strongly suggest that
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sucrose and HFCS are likely major risk factors for NAFLD.
The Discovery of NAFLD and Its Association with Metabolic Syndrome

An association of diabetes with liver disease and gout has been known for over 120 years
(18) and is strongly associated with insulin resistance. Type 2 diabetes mellitus is the
strongest predictor for NAFLD-related hepatic fibrosis and cirrhosis (19). However, the
recognition that people with obesity and prediabetes could develop NAFLD emerged only in
the last several decades (20–22). Many patients with NAFLD show characteristics observed
in subjects with metabolic syndrome, including elevated plasma triglycerides, low HDL
cholesterol, impaired fasting glucose levels, an increased waist circumference, and elevated
blood pressure (23). Indeed, NAFLD can be viewed as another clinical manifestation of
metabolic syndrome, similar to that of hyperuricemia, systemic inflammation (elevated C
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reactive protein), and microalbuminuria.
NAFLD was not recognized as a clinical entity until the 1980s (20–22), but has been
increasing in prevalence, and may progress to nonalcoholic steatohepatitis (NASH) or
cirrhosis and eventual liver transplantation (24, 25). NAFLD is also the most common
chronic liver disease in children and adolescents especially in obese patients and has even
been detected in infants of mothers with gestational diabetes, making this disorder relevant
across a wide spectrum of ages (26–28). Thus, identifying the etiologies of NAFLD
represents a major goal.
Soft Drinks and Added Sugar are Associated with Fatty Liver
While fructose is present in honey and fruits, the major source of fructose is from sucrose
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and HFCS, especially in sugary sweetened beverages. While sucrose containing drinks have
equal amounts of glucose and fructose, HFCS-containing beverages have varying ratios,
usually varying from a 55/45 or 65/35 fructose:glucose ratio (29).
Experimental Studies
Dietary fructose, sucrose, or HFCS have been shown to have a special tendency to induce
fatty liver in experimental animals (6, 17, 30–34), as well as inflammation (35). To develop
the fatty liver, it usually takes atleast 8–24 weeks on high fructose diet with more
progressive disease with longer exposure (36). Often the administration of fructose also
induces other features of metabolic syndrome as well, including elevated blood pressure,
elevated serum triglycerides, and insulin resistance (37). In part the fatty liver may be due to
increased energy intake, as high fructose intake induces leptin resistance in rats (38, 39).
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However, if diet is controlled so that the control group ingests the same amount of total
energy, the fructose-fed rats will still develop features of metabolic syndrome, although
weight gain will not be different between groups (37, 40). Indeed, one can even induce fatty
liver with a calorically restricted diet if the diet is high (40%) in sugar (41). Others have also
reported that high fructose diet can induce fatty liver in the absence of weight gain (35).

Fructose has also been administered to primates. In one study in cynomolgus monkeys (M.
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fascicularis), the administration of fructose was shown to result in both an increase in liver
fat and hepatic fibrosis after seven years, with the degree of fibrosis correlating with time of
fructose exposure (42). Fructose-induced metabolic syndrome can also be induced in rhesus
monkeys (43).
Based on comparative studies in which isocaloric diets were administered using sucrose
(glucose-fructose disaccharide) or a 50:50 mixture of glucose and fructose monosaccharides,
the monosaccharide mixture appears to induce more fatty liver, although the differences are
slight (34). This may relate to differences in absorption or other pharmacokinetics.
Endogenously generated fructose may also have a role in fatty liver and NAFLD (44). For
example, the administration of high concentrations of glucose in drinking water will lead to
obesity, insulin resistance and fatty liver in mice over time (44). Our group reported that the
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high portal vein levels of glucose can induce the expression of aldose reductase in the liver,
which can convert the glucose to sorbitol, which is then further metabolized to fructose by
sorbitol dehydrogenase (the polyol pathway). Indeed, glucose fed mice show increased
fructose levels in their liver, and when fructose metabolism is blocked (by giving glucose to
fructokinase knockout mice) the animals are almost completely protected from fatty liver
and insulin resistance, and are partially protected from obesity (44).
The NAFLD so commonly observed in diabetes may also represent the effects of
endogenous fructose accumulation. Indeed, either knocking down aldose reductase mRNA
in the liver, or treatment with aldose reductase inhibitors, can attenuate hepatic steatosis in
the type 2 diabetic (db db) mouse (45).
Clinical Studies
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Sugary sweetened beverage drink intake is also strongly associated with NAFLD in humans.
Ouyang et al. (11) compared NAFLD subjects without cirrhosis to controls that were
matched for age, sex and BMI. Subjects with NAFLD had a 2 to 3-fold higher intake of
fructose from sugary sweetened beverages than controls, and this was associated with an
increased expression of fructokinase in the liver (11). Subsequently the association of
fructose from soft drinks has been associated with NAFLD in children, adolescents and
adults, where it correlates in a dose-dependent manner with the severity of hepatic fibrosis
(11, 13, 46–52). Fructose intake has also been shown to predict the development of NAFLD
(53).
Clinical studies also suggest a role for fructose in NAFLD. For example, the administration
of sugary beverages for 6 months to humans resulted in increases in liver fat confirmed by
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magnetic resonance spectroscopy (54). Conversely, the restriction of fructose for 9 days in
children with a high baseline fructose intake resulted in both a reduction in liver fat and de
novo lipogenesis compared to controls fed an isocaloric diet (55). In a subset of the same
study, there was also an improvement in other features of the metabolic syndrome, including
diastolic blood pressure, serum triglycerides and insulin resistance (56).

While the experimental and clinical studies suggest an association of fructose intake with
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NAFLD, there is one epidemiological study from Finland that found an inverse relationship
between fructose intake and NAFLD, but in this population less than 10 percent consumed
soft drinks, and fruit intake was much more prevalent (57). While fruits contain fructose,
they are less likely to induce metabolic syndrome due to the lower fructose content per fruit
(compared to a soft drink) and also because they contain constituents (flavonols, epicatechin,
ascorbate, and other antioxidants) that may combat the effects of fructose (58).
In addition to the aforementioned clinical studies, Figure 1 shows the rise in documented
NAFLD prevalence in the National Health and Nutrition Examination Survey (NHANES)
database, using a validated, noninvasive measurement (59), the United States Fatty Liver
Index (US FLI), in relationship to the rise in obesity and also the rise in added sugar
consumption (refined beet, and sugar cane sucrose and HFCS) intake in the periods from
1988–1991, 1999–2000, 2003–2004 and 2011–2012 (60–62). As can be seen, there is a
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definite association between fructose intake from added sugars and the rise in obesity and
NAFLD.
Fructose Effect on Lipogenesis and Fat Oxidation

Fructose intake has been shown to stimulate de novo lipogenesis in animals, as well as to
block hepatic β-fatty acid oxidation (16, 17, 63). Similarly, studies in humans have also
shown that fructose stimulates de novo lipogenesis and blocks fatty acid oxidation in the
liver (13, 63–66). Acutely (hours) fructose stimulates thermogenesis and metabolic rate (67,
68), but chronically fructose (days to weeks) has been shown to reduce resting energy
expenditure (66). The mechanisms for these effects are discussed below, but it is readily
evident how these processes could lead to fat accumulation in the liver and elsewhere.
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Differences in Fructose and Glucose Metabolism

In order to understand how fructose intake might predispose to the development of fatty
liver, one must know how fructose metabolism is distinct from glucose metabolism. Glucose
is metabolized primarily by glucokinase or hexokinase, whereas fructose is principally
metabolized by fructokinase. Fructokinase utilizes ATP to phosphorylate fructose to
fructose-1-phosphate, followed by the metabolism by aldolase B to generate D-
glyceraldehyde and dihydroxyacetone phosphate. From this stage on, fructose metabolism is
similar to glucose metabolism, and results in the generation of glucose, glycogen, and
triglycerides (69). Thus, the unique aspect of fructose metabolism lies in its first two
enzymatic steps (Figure 2).
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The principal isoform of fructokinase in the liver is fructokinase C, which phosphorylates

fructose rapidly and without any negative feedback control, resulting in a drop of ATP and
intracellular phosphate (70–73). The fall in intracellular phosphate activates the enzyme,
adenosine monophosphate (AMP) deaminase, that converts AMP to inosine monophosphate
(IMP), resulting in purine nucleotide turnover that culminates in the formation of uric acid
(74). Fructose also stimulates the synthesis of uric acid from amino acid precursors (75, 76).
The ability of fructose to induce ATP depletion was shown in humans with both intravenous

(49, 70, 77, 78) and orally (79) administered fructose. Likewise, an acute rise in uric acid
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also occurs following fructose ingestion (80–82).
Thus, the unique aspect of fructose compared to glucose is that when fructose is metabolized
there is a transient decrease in intracellular phosphate and ATP levels associated with
nucleotide turnover and uric acid generation. This fall in ATP level induces a series of
reactions, including a transient block in protein synthesis, an induction in oxidative stress,
and mitochondrial dysfunction that turn out to have a key role in fructose-mediated effects
(17, 70, 83).
Fructokinase, the Principal Enzyme Driving Fructose-Induced Fatty Liver

As mentioned, the hepatic metabolism of fructose by fructokinase C results in the
breakdown of AMP to IMP and the generation of uric acid (Figure 2), which is primarily
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due to a fall in intracellular phosphate that occurs following the rapid phosphorylation of
fructose by fructokinase C in the liver (70, 71). In contrast, fructokinase A is a second
isoform of fructokinase and is more ubiquitously expressed, but differs from fructokinase C
in that it phosphorylates fructose less efficiently and does not cause significant ATP
depletion (84, 85). We have observed that mice lacking both fructokinase C and A are
protected from fructose-induced fatty liver, while fructokinase A-knockout mice develop
worse fatty liver compared to wild type animals despite ingesting similar amounts of
fructose (85). These animals also show evidence for greater metabolism of fructose through
the fructokinase C pathway and have higher intrahepatic uric acid levels (85). In addition,
another study by Softic, et al. (85) found fructose, but not glucose drove lipogenic enzymes,
and insulin resistance through fructokinase, and that fructokinase levels are elevated in
fructose fed mice as well as obese humans with NASH (86). Thus, these studies suggest that
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there is a unique property of the fructokinase C pathway that leads to hepatic steatosis, and
raises the possibility that it may relate to the transient ATP depletion, intracellular phosphate
depletion or uric acid generation (16).
Gut Permeability and the Microbiome

One potential mechanism by which fructokinase may drive fatty liver is via actions on the
gut. While fructokinase C is the main enzyme in the liver that metabolizes fructose, it is also
highly expressed in the small intestine. We have found that the metabolism of fructose in the
intestine results in disruption of the tight junctions and that this is not observed in
fructokinase knockout mice (87). This likely is responsible for the increased gut
permeability that has been observed with fructose ingestion (88, 89). Indeed, studies by
Bergheim’s group have shown that the increase in gut permeability results in endotoxin
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getting into the portal vein, which is an important trigger for fatty liver formation (90).
Indeed, the administration of antibiotics to reduce the endotoxemia can improve the fatty
liver (88, 89). Endotoxemia has also been shown to be elevated in children with NAFLD
(91). Thus, the microbiome may have a role in fructose-induced fatty liver through an
interaction with fructose metabolism in the intestinal wall. Finally, fructose has been found
to alter the gut microbiome, which also favors NAFLD development along with increased
gut permeability through loss of tight junctions leading to more progressive disease (92–94).

Role of the Immune System

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As noted, endotoxemia has been identified as a mechanism by which fructose may augment
NAFLD (88). Endotoxemia acts in part by activating the innate immune system, and
inflammation is known to have a role in NAFLD, especially for the transition from steatosis
to steatohepatitis and cirrhosis (95). In this regard, a role for T cells and NK cells (but not B
lymphocytes) in fructose-induced NAFLD has been shown experimentally through the use
of mice genetically modified that lack T cell or NK cell function (96).
Uric acid and its Role in Fructose-Mediated NAFLD

Fructose generates Uric acid—As discussed earlier, fructose is the only common
carbohydrate that generates uric acid during its metabolism (Figure 2), and levels rise in the
circulation within minutes, and can be noted postprandially in subjects eating fructose-rich
meals (80, 82, 97). Fructose also increases uric acid levels in the liver (17). Fructose also
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stimulates the synthesis of uric acid from amino acid precursors (75, 76), and diets high in
fructose are associated with increases in fasting serum uric acid levels (98). Some, but not all
epidemiological studies, have also linked high fructose intake with increases in fasting
serum uric acid (99, 100).
Experimental studies—One of the striking findings was the observation that fructose-
induced metabolic syndrome could be partially inhibited by treatment with allopurinol, a
xanthine oxidase inhibitor that blocks uric acid generation (37). Subsequent studies showed
that xanthine oxidase inhibitors such as allopurinol or febuxostat could reduce fatty liver
from fructose (33) as well as in a genetic model of NAFLD (101), diabetes-induced fatty
liver (102), high fat diet associated NAFLD (103), and alcohol-induced fatty liver (104).
This effect appears to be mediated by improvement of uric acid and/or effects of blocking
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xanthine oxidase-induced oxidative stress. Furthermore, acutely raising uric acid by the
administration of a uricase inhibitor resulted in an acute increase in liver triglycerides and
hepatic expression of fatty acid synthase (FAS) (105), and incubation of liver cells (HepG2
cells) with uric acid also resulted in an increase in intracellular triglycerides (17, 83).
Additional studies identified potential mechanisms by which fructose-induced rise in uric

acid can stimulate hepatic lipogenesis. First, fructose was found to induce mitochondrial
oxidative stress that was mediated by uric acid-induced activation of NADPH oxidase with
its translocation to mitochondria (17). The mitochondria contains a large number of
enzymes, but two in particular are known to be sensitive to oxidative stress, that being
aconitase-2 (in the Kreb cycle) and enoyl CoA hydratase (involved in β-fatty acid oxidation)
(106, 107). Fructose and uric acid have been shown to reduce aconitase-2 activity, leading to
an accumulation of citrate that moves into the cytoplasm and activates lipogenesis by
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stimulating ATP citrate lyase (17). Choi et al. (82) further showed that the initial oxidative
stress in the mitochondria is due to NADPH oxidase, but later there is stimulation of
mitochondrial oxidative stress via the electron transport chain, and that these lead to
endoplasmic reticulum (ER) stress, the activation of SREBP-1c, and further stimulation of
lipogenesis via activation of acetyl CoA carboxylase-1 and FAS (83). Others have also
shown fructose-induced induction of the transcription factor, SREBP-1c (83, 108–110) as
well as the carbohydrate Responsive-Element Binding Protein (ChREBP) (33, 111). The

stimulation of ChREBP results in the stimulation of glucose-6-phosphatase that may mediate

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some of the gluconeogenic effects of fructose (112).
We also documented that fructose-induced uric acid can impair fatty acid oxidation. While
mitochondrial oxidative stress may be partially responsible for lowering enoyl CoA
hydratase-1 activity, we also found that the activity of this enzyme is regulated by AMP-
activated protein kinase (AMPK) and AMP Deaminase-2 (AMPD) (16). As mentioned, the
rapid metabolism of fructose leads to intracellular phosphate, GTP and ATP depletion, with
the stimulation of both AMPK and AMPD activity. However, the stimulation of AMPD
tends to dominate, possibly by removing AMP substrate, but also by generating uric acid
which feeds back to inhibit AMPK (16, 113). The combined effects of inhibition of AMPK,
coupled with AMPD overactivity, results in an inhibition of enoyl A CoA hydratase and the
accumulation of lipid (16), as well as the stimulation of gluconeogenesis (113).
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This process of reducing AMPK and stimulating AMPD can also result in a reduction in
hepatic intracellular ATP levels. Baseline resting ATP levels are low in diabetic subjects with
NAFLD and fall further following fructose challenge (77). Subjects with NAFLD who have
a higher serum uric acid level show a greater fall in ATP levels following the same fructose
challenge (49). Thus, one potential consequence of uric acid is that it may have a role not
only in stimulating lipogenesis and gluconeogenesis, but also in blocking fatty acid
oxidation, and this may lead to a relatively low hepatic ATP state.
Thus these studies document that the lipogenic response to fructose is not from metabolism
of the fructose molecule itself, but rather from the general stimulation of lipogenesis with a
block in fatty acid oxidation. Thus, studies using labeled acetate document lipogenesis better
(65) than by following labeled fructose (9, 10).
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Soluble uric acid has also been shown to have other proinflammatory effects that could play
a role in NAFLD, including the activation of the transcription factor NFκB, stimulation of
chemokines such as monocyte chemoattractant protein-1, and the stimulation of NOD-like
receptor family pyrin domain containing 3 (NLRP3) inflammasomes (114, 115).
Clinical Studies—Epidemiological studies have also linked hyperuricemia with NAFLD

in both adults (11, 116–122) and children (117–119) in both cross-sectional and longitudinal
studies (123, 124) (Table 1). A liver biopsy study also found that in subjects with NAFLD,
the higher the serum uric acid the greater the NAFLD score, lobular inflammation and
steatosis grade (122). In addition, a meta-analysis found a dose-dependent rise in incidence
of NAFLD by 3% for every 1 mg/dL increase in serum uric acid, even after accounting for
factors of the metabolic syndrome and other lifestyle factors (125). Finally, a larger meta-
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analysis of 55,573 patients found a OR of 1.92 (1.59–2.31) for NAFLD occurrence when
comparing the highest to lowest serum uric acid (126). While most subjects with NAFLD
are obese, NAFLD can also occur in subjects with normal and low BMI, and elevated uric
acid also is common in these subjects (17, 127).
Hyperuricemia is also associated with NASH, the intermediate stage and progressive form of
NAFLD. In a study of adolescents, hyperuricemia independently predicted [OR 2.5 (1.87–

2.83)] the presence of NASH after adjusting for age, sex and other components of the
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metabolic syndrome (51). Hyperuricemia in males has also been found to associate more
strongly with NASH than simple steatosis and was significantly associated with hepatocyte
ballooning, BMI, and younger age in multivariate analysis (128).
One small randomized controlled study evaluated patients with ultrasound-diagnosed

NAFLD to determine whether allopurinol treatment (n=17) was superior to placebo (N=14).
They reported significant reductions in cytokeratin 18 (a marker for hepatic apoptosis and
NASH (129)) (P=0.006), lower ALT and AST levels (P<0.001 and P=0.013), and improved
total cholesterol and triglycerides levels (P=0.01 and P=0.038) at 3 months (130).
A diagram showing how fructose with its metabolite uric acid may play a role in NAFLD is
shown in Figure 3. This does not include a larger role uric acid likely plays in the metabolic
syndrome including effects on adipose tissue and islet cells (131).
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Modulating Factors
Factors that may Exacerbate Fructose-induced NAFLD
High fat diets may also contribute to fatty liver. Indeed, when fructose is combined with high
fat diet, much more severe fatty liver occurs in mice (132). One potential mechanism is that
high fat diets also induce mitochondrial oxidative stress (133), similar to fructose.
Nevertheless, mice lacking fructokinase show marked protection from fatty liver and insulin
resistance, documenting the key role for fructose in western diet-induced NAFLD (132).
Alcohol ingestion also is well known to induce fatty liver and chronic liver disease that can
be histologically similar to NAFLD. Alcohol combined with fructose was associated with
worsening metabolic features (hyperlipidemia), although interestingly there did not appear
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to be a synergistic effect on inducing liver injury (134).
As mentioned, high glycemic diets can induce endogenous fructose production (44).
However, we have found that high salt diets can also induce hepatic aldose reductase
expression (due to effects on osmolarity) leading to endogenous fructose production and
NAFLD in mice, and mice lacking fructokinase are protected (Lanaspa MA, manuscript
under review). High salt diets are independently associated with metabolic syndrome/
diabetes (135, 136) and NAFLD (137). Thus, it seems likely that both high glycemic diets
and/or high salt diets might exacerbate fructose-induced NAFLD.
In addition, genetic factors also likely play a role in fructose-induced NAFLD. For instance,
Hispanic children who were homozygous for the patatin-like phospholipase domain-
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containing protein 3 (PNPLA3) gene variant rs738409 were found to have a positive
correlation between liver fat content and carbohydrate (r=0.38, p=0.02) and total sugar
(r=0.33, p=0.04) intake (138). A similar correlation was made in Italian adolescents with the
variant and liver fat content and SSB intake (139). Also of note in 18 adult NAFLD patients
(matched for liver fat content), a 6 day low calorie, low carbohydrate diet revealed
reductions in liver fat content, but was 2.5 fold greater in those who were PNPLA3 GG
homozygotes (n=8) vs CC homozygotes (n=10) (140). Less is known about interaction with

other genes such as transmembrane 6 superfamily member 2 (TM6SF2) which regulates

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VLDL secretion and Glucokinase Regulatory Gene (GCKR) that regulates glycolytic
pathway. Overall, further investigations are warranted in this area, but initial data suggest a
role of genetic polymorphisms interacting with fructose in the pathogenesis of NAFLD.
Protective Factors for Fructose-Induced NAFLD

Omega 3 fatty acids, such as found in fish oils and in Mediterranean diets, may also protect
against NAFLD (141). For example, mice on a western diet (high fat, high fructose) were
partially protected from developing NAFLD if they were supplemented with combined
omega-3 fatty acids with flavanols (142). Likewise, fish oil treatment was found to improve
hypertriglyceridemia and insulin resistance in fructose-fed macaques, although liver fat was
not assessed in that study (143). A short term fructose feeding study in humans also
suggested fish oil might blunt the development of hypertriglyceridemia and de novo
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lipogenesis (64). Further studies investigating this pathway are needed.
Likewise, there is evidence that many substances found in natural fruits, such as the
flavanols, epicatechin, vitamin C and other antioxidants may also protect against fructose-
induced metabolic syndrome (58, 144, 145). This may explain why intake of natural fruits
are not associated with NAFLD. Fruit juices, which are associated with metabolic syndrome,
contain higher amounts of fructose and are often ingested rapidly, leading to higher fructose
concentrations that would cause greater ATP consumption and depletion.
Other Amplifying Mechanisms

High Sugar Exposure May Enhance the Metabolic Effects of Fructose—
Repeated exposure to sugar is known to upregulate the transport of fructose through the
Glut5 transporter (41, 146) and also increase fructokinase levels in the liver (41). Uptake of
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fructose is also enhanced by glucose (147). Interestingly, this may increase the risk for fatty
liver. A study by Sullivan et al investigated the absorption of fructose in lean children, obese
children, and obese children with biopsy proven NAFLD. While fructose malabsorption was
common in lean children, it was less in obese children and children with NAFLD absorbed
almost all of the oral fructose challenge (119). In addition, blood levels of fructose were
lower in the obese children with NAFLD, suggesting they also metabolized the fructose
more rapidly. Furthermore, Jin et al reported that children with NAFLD show a greater rise
in serum triglycerides in response to fructose compared to lean controls (148).
Uric acid as an Amplification Mechanism—An elevated serum uric acid may also
function to amplify fructose effects by creating a positive feedback system. For example,
uric acid may feedback to increase endogenous fructose production by stimulating AR (149,
Author Manuscript
150) and may also stimulate fructose metabolism by increasing expression and activity of
fructokinase (33). In contrast, high concentrations of uric acid can block xanthine oxidase
(151, 152). Thus, high concentrations of uric acid may act to stimulate upstream metabolism
of fructose and which will further promote purine metabolism end-products including uric
acid.

Limitations
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While the evidence for fructose as a risk factor for NAFLD seems very likely, large clinical
trials are still lacking. Nevertheless, there are some groups that have argued that fructose
intake may not increase the risk for NAFLD, especially in short term (4 weeks or less) trials
that compare fructose to isocaloric diets (153) as well as in studies in which fructose-
associated hypercaloric diets (154). However, the development of fatty liver with fructose
takes months in animals (85, 132) and most of the trials were probably too short to note this
effect. Table 2 lists some of these trials, with the longest ones done by Stanhope, et al. and
Maersk, et al. at 10 weeks and 6 months respectively showing differences in either visceral
fat, or liver and visceral fat being higher in fructose diet compared to glucose or other
isocaloric beverage despite similar changes in weight. Other studies noted are shorter
duration, although the majority supports fructose worsening lipid profiles or insulin
sensitivity compared to glucose that are likely mechanisms in the development of NAFLD.
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Of note, studies funded by the food industry, and/or in which the authors are funded by the
food industry, often fail to show a relationship between sugar intake and metabolic disease
(155, 156).
Experimentally, the data that uric acid may have a role in NAFLD is countered by a report in
which exogenously administered uric acid reversed hepatic steatosis since it can function as
an antioxidant (157). However, there may be differences from exogenous uric acid from
intracellular uric acid in terms of its effects on oxidative stress (17, 158). Finally, there is
still much to learn about fructose metabolism that is not well understood. For example,
fructose is now known to stimulate FGF21, which may counter some of the negative effects
of fructose on craving, metabolic syndrome and liver disease (159, 160). Identifying how
this factor modulates fructose responses is clearly of major interest.
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Conclusions
In summary, there has been a marked rise in sugar and HFCS intake that has paralleled the
rise of NAFLD. Experimentally the fructose component of sugar and HFCS appears to have
a major role in inducing fatty liver by both stimulating de novo lipogenesis and blocking β-
fatty acid oxidation. Evidence suggests these effects are due to the unique metabolism of
fructose by fructokinase that leads to a fall in ATP with nucleotide turnover and uric acid
generation. The prooxidative and proinflammatory effects of uric acid lead to increases in
gut permeability and endotoxemia that exacerbates the lipogenic process in the liver, and
coupled with mitochondrial dysfunction results in NAFLD. Clinically the intake of sugary
sweetened beverages is strongly linked with NAFLD. Reducing sugar or HFCS intake may
have a major benefit on NAFLD. Clinical studies to investigate the potential benefit of
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lowering uric acid should also be performed. While there are many causes of NAFLD, the
intake of fructose containing sugars is likely to have a major role.
Acknowledgments
Grant Funding: AMD and MFA receive funding support from NIH/NIDDK (PI: Diehl; DK 061703-09 and MPI:
Abdelmalek: R01DK093568). KDH is supported by a grant of National Research Foundation of Korea (NRF) grant
funded by the Korea government (MSIP) (NRF-2015R1A2A1A15053374, NRF-2017R1A2B2005849).

Abbreviations
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NAFLD Nonalcoholic Fatty Liver Disease
NASH Nonalcoholic steatohepatitis
HFCS high fructose corn syrup
NHANES National Health and Nutrition Examination Survey
US FLI United States Fatty Liver Index
FAS fatty acid synthase
AMPD AMP-activated protein kinase, AMP Deaminase 2
NLRP3 NOD-like receptor family pyrin domain containing 3

Author Manuscript
AR aldose reductase
SDH sorbitol dehydrogenase
PNPLA3 patatin-like phospholipase domain-containing protein 3
TM6SF2 transmembrane 6 superfamily member 2
GCKR Glucokinase Regulatory Gene
References
1. Saab KR, Kendrick J, Yracheta JM, Lanaspa MA, Pollard M, Johnson RJ. New Insights on the Risk
for Cardiovascular Disease in African Americans: The Role of Added Sugars. J Am Soc Nephrol.
Author Manuscript
2014
2. Yracheta JM, Alfonso J, Lanaspa MA, Roncal-Jimenez C, Johnson SB, Sanchez-Lozada LG, et al.
Hispanic Americans living in the United States and their risk for obesity, diabetes and kidney
disease: Genetic and environmental considerations. Postgrad Med. 2015; 127(5):503–10. [PubMed:
25746679]
3. Yracheta JM, Lanaspa MA, Le MT, Abdelmalak MF, Alfonso J, Sanchez-Lozada LG, et al. Diabetes
and Kidney Disease in American Indians: Potential Role of Sugar-Sweetened Beverages. Mayo Clin
Proc. 2015; 90(6):813–23. [PubMed: 26046414]
4. Johnson RJ, Lanaspa MA, Sanchez-Lozada LG, Rivard CJ, Bjornstad PS, Merriman T, et al. Fat
storage syndrome in Pacific peoples: a combination of environment and genetics? Pac Health
Dialog. 2014; 20(1):11–6. [PubMed: 25928990]
5. Macdonald I. Influence of fructose and glucose on serum lipid levels in men and pre- and
postmenopausal women. Am J Clin Nutr. 1966; 18(5):369–72. [PubMed: 4951521]
6. al-Nagdy S, Miller DS, Yudkin J. Changes in body composition and metabolism induced by sucrose
Author Manuscript
in the rat. Nutr Metab. 1970; 12(4):193–219. [PubMed: 5494658]

7. Laube H, Klor HU, Fussganger R, Pfeiffer EF. The effect of starch, sucrose, glucose and fructose on
lipid metabolism in rats. Nutr Metab. 1973; 15(4):273–80. [PubMed: 4795957]
8. Maruhama Y, Macdonald I. Incorporation of orally administered glucose-U-14C and fructose-
U-14C into the triglyceride of liver, plasma, and adipose tissue of rats. Metabolism. 1973; 22(9):
1205–15. [PubMed: 4726370]
9. Nikkila EA. Control of plasma and liver triglyceride kinetics by carbohydrate metabolism and
insulin. Adv Lipid Res. 1969; 7:63–134. [PubMed: 4899909]

10. Sun SZ, Empie MW. Fructose metabolism in humans - what isotopic tracer studies tell us. Nutr
Metab (Lond). 2012; 9(1):89. [PubMed: 23031075]
Author Manuscript
11. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, et al. Fructose consumption as a
risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008; 48(6):993–9. [PubMed:
18395287]
12. Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver disease. Hepatology. 2013; 57(6):
2525–31. [PubMed: 23390127]
13. Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the
pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010; 7(5):
251–64. [PubMed: 20368739]
14. Stanhope KL, Schwarz JM, Havel PJ. Adverse metabolic effects of dietary fructose: results from
the recent epidemiological, clinical, and mechanistic studies. Curr Opin Lipidol. 2013; 24(3):198–
206. [PubMed: 23594708]
15. Le KA, Tappy L. Metabolic effects of fructose. Curr Opin Clin Nutr Metab Care. 2006; 9(4):469–
75. [PubMed: 16778579]
16. Lanaspa MA, Cicerchi C, Garcia G, Li N, Roncal-Jimenez CA, Rivard CJ, et al. Counteracting
Author Manuscript
roles of AMP deaminase and AMP kinase in the development of fatty liver. PLoS One. 2012;
7(11):e48801. [PubMed: 23152807]
17. Lanaspa MA, Sanchez-Lozada LG, Choi YJ, Cicerchi C, Kanbay M, Roncal-Jimenez CA, et al.
Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role
in fructose-dependent and -independent fatty liver. J Biol Chem. 2012; 287(48):40732–44.
[PubMed: 23035112]
18. Harley G. Remarks on Diabetes and Gout in their Relationship to Liver Disease, with Hints
Regarding their Scientific Treatment. Br Med J. 1893; 1(1691):1097–101.
19. Frankel JJ, Asbury CE Jr, Baker LA. Hepatic insufficiency and cirrhosis in diabetes mellitus. AMA
Arch Intern Med. 1950; 86(3):376–90. [PubMed: 14770569]
20. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic
experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980; 55(7):434–8. [PubMed:
7382552]
21. Spech HJ, Liehr H, Mitschke H. Nonalcoholic fatty liver hepatitis and fatty cirrhosis mimicking
Author Manuscript
alcoholic liver diseases. Z Gastroenterol. 1983; 21(11):651–9. [PubMed: 6659631]

22. Diehl AM, Goodman Z, Ishak KG. Alcohollike liver disease in nonalcoholics. A clinical and
histologic comparison with alcohol-induced liver injury. Gastroenterology. 1988; 95(4):1056–62.
[PubMed: 3410220]
23. Paschos P, Paletas K. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia. 2009;
13(1):9–19. [PubMed: 19240815]
24. Calzadilla Bertot L, Adams LA. The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J
Mol Sci. 2016; 17(5)
25. Ray K. NAFLD-the next global epidemic. Nat Rev Gastroenterol Hepatol. 2013; 10(11):621.
[PubMed: 24185985]
26. Mosca A, Della Corte C, Sartorelli MR, Ferretti F, Nicita F, Vania A, et al. Beverage consumption
and paediatric NAFLD. Eat Weight Disord. 2016; 21(4):581–8. [PubMed: 27565159]
27. Love-Osborne KA, Nadeau KJ, Sheeder J, Fenton LZ, Zeitler P. Presence of the metabolic
syndrome in obese adolescents predicts impaired glucose tolerance and nonalcoholic fatty liver
disease. J Adolesc Health. 2008; 42(6):543–8. [PubMed: 18486862]
Author Manuscript
28. Brumbaugh DE, Tearse P, Cree-Green M, Fenton LZ, Brown M, Scherzinger A, et al. Intrahepatic
fat is increased in the neonatal offspring of obese women with gestational diabetes. J Pediatr. 2013;
162(5):930–6. e1. [PubMed: 23260099]
29. Ventura EE, Davis JN, Goran MI. Sugar content of popular sweetened beverages based on
objective laboratory analysis: focus on fructose content. Obesity (Silver Spring). 2011; 19(4):868–
74. [PubMed: 20948525]
30. Bruckdorfer KR, Khan IH, Yudkin J. Dietary carbohydrate and fatty acid synthetase activity in rat
liver and adipose tissue. Biochem J. 1971; 123(2):7P.

31. Ackerman Z, Oron-Herman M, Grozovski M, Rosenthal T, Pappo O, Link G, et al. Fructose-

induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction.
Author Manuscript
Hypertension. 2005; 45(5):1012–8. [PubMed: 15824194]

32. Collison KS, Maqbool ZM, Inglis AL, Makhoul NJ, Saleh SM, Bakheet RH, et al. Effect of dietary
monosodium glutamate on HFCS-induced hepatic steatosis: expression profiles in the liver and
visceral fat. Obesity (Silver Spring). 2010; 18(6):1122–34. [PubMed: 20111022]
33. Lanaspa MA, Sanchez-Lozada LG, Cicerchi C, Li N, Roncal-Jimenez CA, Ishimoto T, et al. Uric
Acid stimulates fructokinase and accelerates fructose metabolism in the development of Fatty liver.
PLoS ONE. 2012; 7(10):e47948. [PubMed: 23112875]
34. Sanchez-Lozada LG, Mu W, Roncal C, Sautin YY, Abdelmalek M, Reungjui S, et al. Comparison
of free fructose and glucose to sucrose in the ability to cause fatty liver. Eur J Nutr. 2010; 49(1):1–
9. [PubMed: 19626358]
35. Schultz A, Neil D, Aguila MB, Mandarim-de-Lacerda CA. Hepatic adverse effects of fructose
consumption independent of overweight/obesity. Int J Mol Sci. 2013; 14(11):21873–86. [PubMed:
24196354]
36. Asgharpour A, Cazanave SC, Pacana T, Seneshaw M, Vincent R, Banini BA, et al. A diet-induced
Author Manuscript
animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J Hepatol. 2016;
65(3):579–88. [PubMed: 27261415]
37. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, et al. A causal role for uric
acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006; 290(3):F625–31.
[PubMed: 16234313]
38. Shapiro A, Mu W, Roncal C, Cheng KY, Johnson RJ, Scarpace PJ. Fructose-induced leptin
resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Regul
Integr Comp Physiol. 2008; 295(5):R1370–5. [PubMed: 18703413]
39. Shapiro A, Tumer N, Gao Y, Cheng KY, Scarpace PJ. Prevention and reversal of diet-induced
leptin resistance with a sugar-free diet despite high fat content. Br J Nutr. 2011; 106(3):390–7.
[PubMed: 21418711]
40. Reungjui S, Roncal CA, Mu W, Srinivas TR, Sirivongs D, Johnson RJ, et al. Thiazide diuretics
exacerbate fructose-induced metabolic syndrome. J Am Soc Nephrol. 2007; 18(10):2724–31.
[PubMed: 17855639]
41. Roncal-Jimenez CA, Lanaspa MA, Rivard CJ, Nakagawa T, Sanchez-Lozada LG, Jalal D, et al.
Author Manuscript
Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess
energy intake. Metabolism. 2011; 60(9):1259–70. [PubMed: 21489572]
42. Cydylo MA, Davis AT, Kavanagh K. Fatty liver promotes fibrosis in monkeys consuming high
fructose. Obesity (Silver Spring). 2017; 25(2):290–3. [PubMed: 28124507]
43. Bremer AA, Stanhope KL, Graham JL, Cummings BP, Wang W, Saville BR, et al. Fructose-fed
rhesus monkeys: a nonhuman primate model of insulin resistance, metabolic syndrome, and type 2
diabetes. Clin Transl Sci. 2011; 4(4):243–52. [PubMed: 21884510]
44. Lanaspa MA, Ishimoto T, Li N, Cicerchi C, Orlicky DJ, Ruzicky P, et al. Endogenous fructose
production and metabolism in the liver contributes to the development of metabolic syndrome. Nat
Commun. 2013; 4:2434. [PubMed: 24022321]
45. Qiu L, Lin J, Xu F, Gao Y, Zhang C, Liu Y, et al. Inhibition of aldose reductase activates hepatic
peroxisome proliferator-activated receptor-alpha and ameliorates hepatosteatosis in diabetic db/db
mice. Exp Diabetes Res. 2012; 2012:789730. [PubMed: 22110479]
46. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Increased fructose
Author Manuscript
consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease.
Hepatology. 2010; 51(6):1961–71. [PubMed: 20301112]
47. Collison KS, Saleh SM, Bakheet RH, Al-Rabiah RK, Inglis AL, Makhoul NJ, et al. Diabetes of the
Liver: The Link Between Nonalcoholic Fatty Liver Disease and HFCS-55. Obesity (Silver Spring).
2009
48. Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K. Fructose: a highly lipogenic nutrient implicated
in insulin resistance, hepatic steatosis, and the metabolic syndrome. Am J Physiol Endocrinol
Metab. 2010; 299(5):E685–94. [PubMed: 20823452]

49. Abdelmalek MF, Lazo M, Horska A, Bonekamp S, Lipkin EW, Balasubramanyam A, et al. Higher
dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese
Author Manuscript
individuals with type 2 diabetes. Hepatology. 2012; 56(3):952–60. [PubMed: 22467259]

50. Nomura K, Yamanouchi T. The role of fructose-enriched diets in mechanisms of nonalcoholic fatty
liver disease. J Nutr Biochem. 2012; 23(3):203–8. [PubMed: 22129639]
51. Mosca A, Nobili V, De Vito R, Crudele A, Scorletti E, Villani A, et al. Serum uric acid
concentrations and fructose consumption are independently associated with NASH in children and
adolescents. Journal of hepatology. 2017; 66(5):1031–6. [PubMed: 28214020]
52. Hamza RT, Ahmed AY, Rezk DG, Hamed AI. Dietary fructose intake in obese children and
adolescents: relation to procollagen type III N-terminal peptide (P3NP) and non-alcoholic fatty
liver disease. J Pediatr Endocrinol Metab. 2016; 29(12):1345–52. [PubMed: 27442361]
53. O’Sullivan TA, Oddy WH, Bremner AP, Sherriff JL, Ayonrinde OT, Olynyk JK, et al. Lower
fructose intake may help protect against development of nonalcoholic fatty liver in adolescents
with obesity. J Pediatr Gastroenterol Nutr. 2014; 58(5):624–31. [PubMed: 24345826]
54. Maersk M, Belza A, Stodkilde-Jorgensen H, Ringgaard S, Chabanova E, Thomsen H, et al.
Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-
Author Manuscript
mo randomized intervention study. Am J Clin Nutr. 2012; 95(2):283–9. [PubMed: 22205311]

55. Schwarz JM, Noworolski SM, Erkin-Cakmak A, Korn NJ, Wen MJ, Tai VW, et al. Effects of
Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children
With Obesity. Gastroenterology. 2017; 153(3):743–52. [PubMed: 28579536]
56. Lustig RH, Mulligan K, Noworolski SM, Tai VW, Wen MJ, Erkin-Cakmak A, et al. Isocaloric
fructose restriction and metabolic improvement in children with obesity and metabolic syndrome.
Obesity (Silver Spring). 2015
57. Kanerva N, Sandboge S, Kaartinen NE, Mannisto S, Eriksson JG. Higher fructose intake is
inversely associated with risk of nonalcoholic fatty liver disease in older Finnish adults. Am J Clin
Nutr. 2014; 100(4):1133–8. [PubMed: 25099548]
58. Vasdev S, Gill V, Parai S, Longerich L, Gadag V. Dietary vitamin E and C supplementation
prevents fructose induced hypertension in rats. Mol Cell Biochem. 2002; 241(1–2):107–14.
[PubMed: 12482032]
59. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty
Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC
Author Manuscript
Gastroenterol. 2006; 6:33. [PubMed: 17081293]

60. Ruhl CE, Everhart JE. Fatty liver indices in the multiethnic United States National Health and
Nutrition Examination Survey. Aliment Pharmacol Ther. 2015; 41(1):65–76. [PubMed: 25376360]
61. An R. Prevalence and Trends of Adult Obesity in the US, 1999–2012. ISRN Obes. 2014;
2014:185132. [PubMed: 25002986]
62. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United
States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord. 1998; 22(1):39–47.
[PubMed: 9481598]
63. Softic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in
Fatty Liver Disease. Dig Dis Sci. 2016; 61(5):1282–93. [PubMed: 26856717]
64. Faeh D, Minehira K, Schwarz JM, Periasamy R, Park S, Tappy L. Effect of fructose overfeeding
and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men.
Diabetes. 2005; 54(7):1907–13. [PubMed: 15983189]
65. Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, et al. Consuming
Author Manuscript
fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and
decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009; 119(5):1322–34.
[PubMed: 19381015]
66. Cox CL, Stanhope KL, Schwarz JM, Graham JL, Hatcher B, Griffen SC, et al. Consumption of
fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in
overweight/obese men and women. Eur J Clin Nutr. 2012; 66(2):201–8. [PubMed: 21952692]
67. Schwarz JM, Acheson KJ, Tappy L, Piolino V, Muller MJ, Felber JP, et al. Thermogenesis and
fructose metabolism in humans. Am J Physiol. 1992; 262(5 Pt 1):E591–8. [PubMed: 1350420]

68. Mizobe T, Nakajima Y, Ueno H, Sessler DI. Fructose administration increases intraoperative core
temperature by augmenting both metabolic rate and the vasoconstriction threshold.
Author Manuscript
Anesthesiology. 2006; 104(6):1124–30. [PubMed: 16732081]

69. Steinmann, B., Gitzelmann, R., Van den Berghe, G. Disorders of Fructose Metabolism. In: Scriver,
C.Beaudet, A.Sly, W., Valle, D., editors. The Metabolic and Molecular Basis of Inherited Disease.
New York: McGraw-Hill; 2001. p. 1489-520.
70. Maenpaa PH, Raivio KO, Kekomaki MP. Liver adenine nucleotides: fructose-induced depletion
and its effect on protein synthesis. Science. 1968; 161(847):1253–4. [PubMed: 5673437]
71. Smith CM, Rovamo LM, Raivio KO. Fructose-induced adenine nucleotide catabolism in isolated
rat hepatocytes. Can J Biochem. 1977; 55(12):1237–40. [PubMed: 597772]
72. van den Berghe G, Bronfman M, Vanneste R, Hers HG. The mechanism of adenosine triphosphate
depletion in the liver after a load of fructose. A kinetic study of liver adenylate deaminase.
Biochem J. 1977; 162(3):601–9. [PubMed: 869906]
73. Kurtz TW, Kabra PM, Booth BE, Al-Bander HA, Portale AA, Serena BG, et al. Liquid-
chromatographic measurements of inosine, hypoxanthine, and xanthine in studies of fructose-
induced degradation of adenine nucleotides in humans and rats. Clin Chem. 1986; 32(5):782–6.
Author Manuscript
[PubMed: 3698269]
74. Van den Berghe G. Fructose: metabolism and short-term effects on carbohydrate and purine
metabolic pathways. Prog Biochem Pharmacol. 1986; 21:1–32.
75. Emmerson BT. Effect of oral fructose on urate production. Ann Rheum Dis. 1974; 33(3):276–80.
[PubMed: 4843132]
76. Raivio KO, Becker A, Meyer LJ, Greene ML, Nuki G, Seegmiller JE. Stimulation of human purine
synthesis de novo by fructose infusion. Metabolism. 1975; 24(7):861–9. [PubMed: 166270]
77. Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP
homeostasis in human nonalcoholic steatohepatitis: a pilot study. Jama. 1999; 282(17):1659–64.
[PubMed: 10553793]
78. Nair S, VPC, Arnold C, Diehl AM. Hepatic ATP reserve and efficiency of replenishing:
comparison between obese and nonobese normal individuals. Am J Gastroenterol. 2003; 98(2):
466–70. [PubMed: 12591070]
79. Bawden SJ, Stephenson MC, Ciampi E, Hunter K, Marciani L, Macdonald IA, et al. Investigating
Author Manuscript
the effects of an oral fructose challenge on hepatic ATP reserves in healthy volunteers: A P MRS
study. Clin Nutr. 2015
80. Perheentupa J, Raivio K. Fructose-induced hyperuricaemia. Lancet. 1967; 2(7515):528–31.
[PubMed: 4166890]
81. Stirpe F, Della Corte E, Bonetti E, Abbondanza A, Abbati A, De Stefano F. Fructose-induced
hyperuricaemia. Lancet. 1970; 2(7686):1310–1. [PubMed: 4098798]
82. Le MT, Frye RF, Rivard CJ, Cheng J, McFann KK, Segal MS, et al. Effects of high-fructose corn
syrup and sucrose on the pharmacokinetics of fructose and acute metabolic and hemodynamic
responses in healthy subjects. Metabolism. 2012; 61(5):641–51. [PubMed: 22152650]
83. Choi YJ, Shin HS, Choi HS, Park JW, Jo I, Oh ES, et al. Uric acid induces fat accumulation via
generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes. Lab Invest.
2014; 94(10):1114–25. [PubMed: 25111690]
84. Diggle CP, Shires M, McRae C, Crellin D, Fisher J, Carr IM, et al. Both isoforms of
ketohexokinase are dispensable for normal growth and development. Physiological genomics.
2010; 42a(4):235–43. [PubMed: 20841500]
Author Manuscript
85. Ishimoto T, Lanaspa MA, Le MT, Garcia GE, Diggle CP, Maclean PS, et al. Opposing effects of
fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad
Sci U S A. 2012; 109(11):4320–5. [PubMed: 22371574]
86. Softic S, Gupta MK, Wang GX, Fujisaka S, O’Neill BT, Rao TN, et al. Divergent effects of glucose
and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest. 2017
87. Johnson RJ, Rivard C, Lanaspa MA, Otabachian-Smith S, Ishimoto T, Cicerchi C, et al.
Fructokinase, Fructans, Intestinal Permeability, and Metabolic Syndrome: An Equine Connection?
J Equine Vet Science. 2013; 33(2):120–6.

88. Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, et al. Antibiotics protect against
fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol. 2008; 48(6):
Author Manuscript
983–92. [PubMed: 18395289]

89. Spruss A, Bergheim I. Dietary fructose and intestinal barrier: potential risk factor in the
pathogenesis of nonalcoholic fatty liver disease. J Nutr Biochem. 2009; 20(9):657–62. [PubMed:
19679262]
90. Thuy S, Ladurner R, Volynets V, Wagner S, Strahl S, Konigsrainer A, et al. Nonalcoholic fatty liver
disease in humans is associated with increased plasma endotoxin and plasminogen activator
inhibitor 1 concentrations and with fructose intake. J Nutr. 2008; 138(8):1452–5. [PubMed:
18641190]
91. Jin R, Willment A, Patel SS, Sun X, Song M, Mannery YO, et al. Fructose induced endotoxemia in
pediatric nonalcoholic Fatty liver disease. Int J Hepatol. 2014; 2014:560620. [PubMed: 25328713]
92. Jegatheesan P, Beutheu S, Freese K, Waligora-Dupriet AJ, Nubret E, Butel MJ, et al. Preventive
effects of citrulline on Western diet-induced non-alcoholic fatty liver disease in rats. Br J Nutr.
2016; 116(2):191–203. [PubMed: 27197843]
93. Jegatheesan P, Beutheu S, Ventura G, Sarfati G, Nubret E, Kapel N, et al. Effect of specific amino
Author Manuscript
acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease. Clin Nutr.
2016; 35(1):175–82. [PubMed: 25736031]
94. Ritze Y, Bardos G, Claus A, Ehrmann V, Bergheim I, Schwiertz A, et al. Lactobacillus rhamnosus
GG protects against non-alcoholic fatty liver disease in mice. PLoS One. 2014; 9(1):e80169.
[PubMed: 24475018]
95. Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/
NASH. Dig Dis Sci. 2016; 61(5):1294–303. [PubMed: 26841783]
96. Bhattacharjee J, Kumar JM, Arindkar S, Das B, Pramod U, Juyal RC, et al. Role of
immunodeficient animal models in the development of fructose induced NAFLD. J Nutr Biochem.
2014; 25(2):219–26. [PubMed: 24445047]
97. Cox CL, Stanhope KL, Schwarz JM, Graham JL, Hatcher B, Griffen SC, et al. Consumption of
fructose- but not glucose-sweetened beverages for 10 weeks increases circulating concentrations of
uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese
humans. Nutr Metab (Lond). 2012; 9(1):68. [PubMed: 22828276]
98. Reiser S, Powell AS, Scholfield DJ, Panda P, Ellwood KC, Canary JJ. Blood lipids, lipoproteins,
Author Manuscript
apoproteins, and uric acid in men fed diets containing fructose or high-amylose cornstarch. Am J
Clin Nutr. 1989; 49(5):832–9. [PubMed: 2497634]
99. Choi JW, Ford ES, Gao X, Choi HK. Sugar-sweetened soft drinks, diet soft drinks, and serum uric
acid level: The third national health and nutrition examination survey. Arthritis Rheum. 2007;
59(1):109–16.
100. Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective
cohort study. Bmj. 2008; 336(7639):309–12. [PubMed: 18244959]
101. Baldwin W, McRae S, Marek G, Wymer D, Pannu V, Baylis C, et al. Hyperuricemia as a mediator
of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the
metabolic syndrome. Diabetes. 2011; 60(4):1258–69. [PubMed: 21346177]
102. Wang W, Wang C, Ding XQ, Pan Y, Gu TT, Wang MX, et al. Quercetin and allopurinol reduce
liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic
rats. Br J Pharmacol. 2013; 169(6):1352–71. [PubMed: 23647015]
103. Nakatsu Y, Seno Y, Kushiyama A, Sakoda H, Fujishiro M, Katasako A, et al. The xanthine
Author Manuscript
oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent

model. Am J Physiol Gastrointest Liver Physiol. 2015; 309(1):G42–51. [PubMed: 25999428]
104. Kono H, Rusyn I, Bradford BU, Connor HD, Mason RP, Thurman RG. Allopurinol prevents early
alcohol-induced liver injury in rats. J Pharmacol Exp Ther. 2000; 293(1):296–303. [PubMed:
10734182]
105. Tapia E, Cristobal M, Garcia-Arroyo FE, Soto V, Monroy-Sanchez F, Pacheco U, et al.
Synergistic effect of uricase blockade plus physiological amounts of fructose-glucose on
glomerular hypertension and oxidative stress in rats. Am J Physiol Renal Physiol. 2013;
304(6):F727–36. [PubMed: 23303409]

106. Addabbo F, Montagnani M, Goligorsky MS. Mitochondria and reactive oxygen species.
Hypertension. 2009; 53(6):885–92. [PubMed: 19398655]
Author Manuscript
107. Addabbo F, Ratliff B, Park HC, Kuo MC, Ungvari Z, Csiszar A, et al. The Krebs cycle and
mitochondrial mass are early victims of endothelial dysfunction: proteomic approach. Am J
Pathol. 2009; 174(1):34–43. [PubMed: 19095954]
108. Herman MA, Samuel VT. The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis.
Trends in endocrinology and metabolism: TEM. 2016; 27(10):719–30. [PubMed: 27387598]
109. Miyazaki M, Dobrzyn A, Man WC, Chu K, Sampath H, Kim HJ, et al. Stearoyl-CoA desaturase 1
gene expression is necessary for fructose-mediated induction of lipogenic gene expression by
sterol regulatory element-binding protein-1c-dependent and -independent mechanisms. J Biol
Chem. 2004; 279(24):25164–71. [PubMed: 15066988]
110. Nagai Y, Yonemitsu S, Erion DM, Iwasaki T, Stark R, Weismann D, et al. The role of peroxisome
proliferator-activated receptor gamma coactivator-1 beta in the pathogenesis of fructose-induced
insulin resistance. Cell Metab. 2009; 9(3):252–64. [PubMed: 19254570]
111. Koo HY, Miyashita M, Cho BH, Nakamura MT. Replacing dietary glucose with fructose
increases ChREBP activity and SREBP-1 protein in rat liver nucleus. Biochem Biophys Res
Author Manuscript
Commun. 2009; 390(2):285–9. [PubMed: 19799862]

112. Kim MS, Krawczyk SA, Doridot L, Fowler AJ, Wang JX, Trauger SA, et al. ChREBP regulates
fructose-induced glucose production independently of insulin signaling. J Clin Invest. 2016;
126(11):4372–86. [PubMed: 27669460]
113. Cicerchi C, Li N, Kratzer J, Garcia G, Roncal-Jimenez CA, Tanabe K, et al. Uric acid-dependent
inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation:
evolutionary implications of the uricase loss in hominids. FASEB J. 2014; 28(8):3339–50.
[PubMed: 24755741]
114. Wan X, Xu C, Lin Y, Lu C, Li D, Sang J, et al. Uric acid regulates hepatic steatosis and insulin
resistance through the NLRP3 inflammasome-dependent mechanism. J Hepatol. 2016; 64(4):
925–32. [PubMed: 26639394]
115. Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, et al. Uric acid stimulates monocyte
chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated
protein kinase and cyclooxygenase-2. Hypertension. 2003; 41(6):1287–93. [PubMed: 12743010]
116. Sirota JC, McFann K, Targher G, Johnson RJ, Chonchol M, Jalal DI. Elevated serum uric acid
Author Manuscript
levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome
features in the United States: Liver ultrasound data from the National Health and Nutrition
Examination Survey. Metabolism. 2013; 62(3):392–9. [PubMed: 23036645]
117. Sartorio A, Del Col A, Agosti F, Mazzilli G, Bellentani S, Tiribelli C, et al. Predictors of non-
alcoholic fatty liver disease in obese children. Eur J Clin Nutr. 2007; 61(7):877–83. [PubMed:
17151586]
118. Vos MB, Colvin R, Belt P, Molleston JP, Murray KF, Rosenthal P, et al. Correlation of vitamin E,
uric acid, and diet composition with histologic features of pediatric NAFLD. J Pediatr
Gastroenterol Nutr. 2012; 54(1):90–6. [PubMed: 22197855]
119. Sullivan JS, Le MT, Pan Z, Rivard C, Love-Osborne K, Robbins K, et al. Oral fructose absorption
in obese children with non-alcoholic fatty liver disease. Pediatr Obes. 2015; 10(3):188–95.
[PubMed: 24961681]
120. Li Y, Xu C, Yu C, Xu L, Miao M. Association of serum uric acid level with non-alcoholic fatty
liver disease: a cross-sectional study. J Hepatol. 2009; 50(5):1029–34. [PubMed: 19299029]
Author Manuscript
121. Kuo CF, Yu KH, Luo SF, Chiu CT, Ko YS, Hwang JS, et al. Gout and risk of non-alcoholic fatty
liver disease. Scand J Rheumatol. 2010; 39(6):466–71. [PubMed: 20560813]
122. Petta S, Camma C, Cabibi D, Di Marco V, Craxi A. Hyperuricemia is associated with histological
liver damage in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2011;
34(7):757–66. [PubMed: 21790685]
123. Lee JW, Cho YK, Ryan M, Kim H, Lee SW, Chang E, et al. Serum uric Acid as a predictor for the
development of nonalcoholic Fatty liver disease in apparently healthy subjects: a 5-year
retrospective cohort study. Gut Liver. 2010; 4(3):378–83. [PubMed: 20981217]

124. Xu C, Yu C, Xu L, Miao M, Li Y. High serum uric acid increases the risk for nonalcoholic Fatty
liver disease: a prospective observational study. PLoS ONE. 2010; 5(7):e11578. [PubMed:
Author Manuscript
20644649]
125. Liu Z, Que S, Zhou L, Zheng S. Dose-response Relationship of Serum Uric Acid with Metabolic
Syndrome and Non-alcoholic Fatty Liver Disease Incidence: A Meta-analysis of Prospective
Studies. Sci Rep. 2015; 5:14325. [PubMed: 26395162]
126. Zhou Y, Wei F, Fan Y. High serum uric acid and risk of nonalcoholic fatty liver disease: A
systematic review and meta-analysis. Clin Biochem. 2016; 49(7–8):636–42. [PubMed:
26738417]
127. Kim HJ, Lee KE, Kim DJ, Kim SK, Ahn CW, Lim SK, et al. Metabolic significance of
nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med. 2004; 164(19):
2169–75. [PubMed: 15505132]
128. Sertoglu E, Ercin CN, Celebi G, Gurel H, Kayadibi H, Genc H, et al. The relationship of serum
uric acid with non-alcoholic fatty liver disease. Clin Biochem. 2014; 47(6):383–8. [PubMed:
24525254]
129. Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18
Author Manuscript
fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter

validation study. Hepatology. 2009; 50(4):1072–8. [PubMed: 19585618]
130. Sylvia, S., Sedhom, OAB., Salama, Salwa H., Mokhles, Mohamad A. Assessment of the
therapeutic effect of allopurinol in patients with non-alcoholic fatty liver disease associated with
hyperuricemia by cytokeratin 18. 9th Euro Global Gastroenterology Conference; Valenica Spain.
2016;
131. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, et al. Sugar, uric
Acid, and the etiology of diabetes and obesity. Diabetes. 2013; 62(10):3307–15. [PubMed:
24065788]
132. Ishimoto T, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Orlicky DJ, Cicerchi C, et al. High-fat
and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase.
Hepatology. 2013; 58(5):1632–43. [PubMed: 23813872]
133. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, et al. Mitochondrial H2O2
emission and cellular redox state link excess fat intake to insulin resistance in both rodents and
humans. J Clin Invest. 2009; 119(3):573–81. [PubMed: 19188683]
Author Manuscript
134. Alwahsh SM, Xu M, Schultze FC, Wilting J, Mihm S, Raddatz D, et al. Combination of alcohol
and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and
insulin resistance in rats. PLoS One. 2014; 9(8):e104220. [PubMed: 25101998]
135. Hu G, Jousilahti P, Peltonen M, Lindstrom J, Tuomilehto J. Urinary sodium and potassium
excretion and the risk of type 2 diabetes: a prospective study in Finland. Diabetologia. 2005;
48(8):1477–83. [PubMed: 15971060]
136. Ma Y, He FJ, MacGregor GA. High salt intake: independent risk factor for obesity? Hypertension.
2015; 66(4):843–9. [PubMed: 26238447]
137. Huh JH, Lee KJ, Lim JS, Lee MY, Park HJ, Kim MY, et al. High Dietary Sodium Intake Assessed
by Estimated 24-h Urinary Sodium Excretion Is Associated with NAFLD and Hepatic Fibrosis.
PLoS One. 2015; 10(11):e0143222. [PubMed: 26571018]
138. Davis JN, Le KA, Walker RW, Vikman S, Spruijt-Metz D, Weigensberg MJ, et al. Increased
hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in
PNPLA3 and high dietary carbohydrate and sugar consumption. Am J Clin Nutr. 2010; 92(6):
Author Manuscript
1522–7. [PubMed: 20962157]

139. Nobili V, Liccardo D, Bedogni G, Salvatori G, Gnani D, Bersani I, et al. Influence of dietary
pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents. Genes
Nutr. 2014; 9(3):392. [PubMed: 24627307]
140. Sevastianova K, Kotronen A, Gastaldelli A, Perttila J, Hakkarainen A, Lundbom J, et al. Genetic
variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat
in humans. Am J Clin Nutr. 2011; 94(1):104–11. [PubMed: 21525193]

141. Simopoulos AP. Dietary omega-3 fatty acid deficiency and high fructose intake in the
development of metabolic syndrome, brain metabolic abnormalities, and non-alcoholic fatty liver
Author Manuscript
disease. Nutrients. 2013; 5(8):2901–23. [PubMed: 23896654]

142. Vauzour D, Rodriguez-Ramiro I, Rushbrook S, Ipharraguerre IR, Bevan D, Davies S, et al. n-3
Fatty acids combined with flavan-3-ols prevent steatosis and liver injury in a murine model of
NAFLD. Biochim Biophys Acta. 2017; 1864(1):69–78. [PubMed: 28986308]
143. Bremer AA, Stanhope KL, Graham JL, Cummings BP, Ampah SB, Saville BR, et al. Fish oil
supplementation ameliorates fructose-induced hypertriglyceridemia and insulin resistance in
adult male rhesus macaques. J Nutr. 2014; 144(1):5–11. [PubMed: 24108131]
144. Hu QH, Zhang X, Pan Y, Li YC, Kong LD. Allopurinol, quercetin and rutin ameliorate renal
NLRP3 inflammasome activation and lipid accumulation in fructose-fed rats. Biochem
Pharmacol. 2012; 84(1):113–25. [PubMed: 22426011]
145. Gutierrez-Salmean G, Meaney E, Lanaspa MA, Cicerchi C, Johnson RJ, Dugar S, et al. A
randomized, placebo-controlled, double-blind study on the effects of (−)-epicatechin on the
triglyceride/HDLc ratio and cardiometabolic profile of subjects with hypertriglyceridemia:
Unique in vitro effects. Int J Cardiol. 2016; 223:500–6. [PubMed: 27552564]
Author Manuscript
146. Korieh A, Crouzoulon G. Dietary regulation of fructose metabolism in the intestine and in the
liver of the rat. Duration of the effects of a high fructose diet after the return to the standard diet.
Arch Int Physiol Biochim Biophys. 1991; 99(6):455–60. [PubMed: 1725750]
147. Rumessen JJ, Gudmand-Hoyer E. Absorption capacity of fructose in healthy adults. Comparison
with sucrose and its constituent monosaccharides. Gut. 1986; 27(10):1161–8. [PubMed:
3781328]
148. Jin R, Le NA, Liu S, Farkas Epperson M, Ziegler TR, Welsh JA, et al. Children with NAFLD are
more sensitive to the adverse metabolic effects of fructose beverages than children without
NAFLD. J Clin Endocrinol Metab. 2012; 97(7):E1088–98. [PubMed: 22544914]
149. Zhang Y, Hong Q, Huang Z, Xue P, Lv Y, Fu B, et al. ALDR enhanced endothelial injury in
hyperuricemia screened using SILAC. Cell Physiol Biochem. 2014; 33(2):479–90. [PubMed:
24556878]
150. Huang Z, Hong Q, Zhang X, Xiao W, Wang L, Cui S, et al. Aldose reductase mediates endothelial
cell dysfunction induced by high uric acid concentrations. Cell Commun Signal. 2017; 15(1):3.
[PubMed: 28057038]
Author Manuscript
151. Radi R, Tan S, Prodanov E, Evans RA, Parks DA. Inhibition of xanthine oxidase by uric acid and
its influence on superoxide radical production. Biochim Biophys Acta. 1992; 1122(2):178–82.
[PubMed: 1322703]
152. Tan S, Radi R, Gaudier F, Evans RA, Rivera A, Kirk KA, et al. Physiologic levels of uric acid
inhibit xanthine oxidase in human plasma. Pediatr Res. 1993; 34(3):303–7. [PubMed: 8134172]
153. Chiu S, Sievenpiper JL, de Souza RJ, Cozma AI, Mirrahimi A, Carleton AJ, et al. Effect of
fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-
analysis of controlled feeding trials. Eur J Clin Nutr. 2014; 68(4):416–23. [PubMed: 24569542]
154. Chung M, Ma J, Patel K, Berger S, Lau J, Lichtenstein AH. Fructose, high-fructose corn syrup,
sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and
meta-analysis. Am J Clin Nutr. 2014; 100(3):833–49. [PubMed: 25099546]
155. Schillinger D, Tran J, Mangurian C, Kearns C. Do Sugar-Sweetened Beverages Cause Obesity
and Diabetes? Industry and the Manufacture of Scientific Controversy. Ann Intern Med. 2016;
165(12):895–7. [PubMed: 27802504]
Author Manuscript
156. Bes-Rastrollo M, Schulze MB, Ruiz-Canela M, Martinez-Gonzalez MA. Financial conflicts of

interest and reporting bias regarding the association between sugar-sweetened beverages and
weight gain: a systematic review of systematic reviews. PLoS medicine. 2013; 10(12):e1001578.
dicsussion e. [PubMed: 24391479]
157. Garcia-Ruiz I, Rodriguez-Juan C, Diaz-Sanjuan T, del Hoyo P, Colina F, Munoz-Yague T, et al.
Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice. Hepatology.
2006; 44(3):581–91. [PubMed: 16941682]

158. Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the
renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-
Author Manuscript
induced endothelial dysfunction. J Hypertens. 2010; 28(6):1234–42. [PubMed: 20486275]

159. Dushay JR, Toschi E, Mitten EK, Fisher FM, Herman MA, Maratos-Flier E. Fructose ingestion
acutely stimulates circulating FGF21 levels in humans. Mol Metab. 2015; 4(1):51–7. [PubMed:
25685689]
160. Fisher FM, Kim M, Doridot L, Cunniff JC, Parker TS, Levine DM, et al. A critical role for
ChREBP-mediated FGF21 secretion in hepatic fructose metabolism. Mol Metab. 2017; 6(1):14–
21. [PubMed: 28123933]
161. Johnston RD, Stephenson MC, Crossland H, Cordon SM, Palcidi E, Cox EF, et al. No difference
between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy
overweight men. Gastroenterology. 2013; 145(5):1016–25. e2. [PubMed: 23872500]
162. Aeberli I, Hochuli M, Gerber PA, Sze L, Murer SB, Tappy L, et al. Moderate amounts of fructose
consumption impair insulin sensitivity in healthy young men: a randomized controlled trial.
Diabetes Care. 2013; 36(1):150–6. [PubMed: 22933433]
163. Lecoultre V, Egli L, Carrel G, Theytaz F, Kreis R, Schneiter P, et al. Effects of fructose and
Author Manuscript
glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans.
Obesity (Silver Spring). 2013; 21(4):782–5. [PubMed: 23512506]
164. Silbernagel G, Machann J, Unmuth S, Schick F, Stefan N, Haring HU, et al. Effects of 4-week
very-high-fructose/glucose diets on insulin sensitivity, visceral fat and intrahepatic lipids: an
exploratory trial. The British journal of nutrition. 2011; 106(1):79–86. [PubMed: 21396140]
165. Schwarz JM, Noworolski SM, Wen MJ, Dyachenko A, Prior JL, Weinberg ME, et al. Effect of a
High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat. J Clin Endocrinol Metab.
2015; 100(6):2434–42. [PubMed: 25825943]
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Lay Summary
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In this paper we discuss the role of fructose, a monosaccharide sugar, in the development
of NonAlcoholic Fatty Liver Disease (NAFLD). We examine evidence both in animal
models, and clinical data to support the notion that fructose is a kye player in the recent
NAFLD epidemic.
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Figure 1.
Association of Added Sugar Consumption with rates of NAFLD, Obesity in NHANES data.
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Figure 2.
Interaction of Fructose, Glucose and Polyol Pathway with uric acid and triglycerides
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Figure 3.
Fructose Mechanism mediating development and progression of NAFLD
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Table 1
Studies with reported Uric Acid in NAFLD patients compared to non-NAFLD patients.
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Study Uric Acid (mg/dL) and NAFLD P Values

Ouyang X, et al. (2008), Journal of NAFLD 6.8 ± 1.6 vs non- NAFLD 4.8 ± 0.9 P=0.03
Hepatology
Sirota JC, et al. (2013), Metabolism Non-NAFLD 5.09 ± 0.02 vs Mild NAFLD 5.19 ± 0.06 vs Moderate NAFLD P<0.0001
5.89 ± 0.06 vs Severe NAFLD 6.35 ± 0.10
Liu J, et al. (2016), Hepatol Res Obese Hyperuricemia (>7.0mg/dL males and >6.0mg/dL females) OR Not calculated
1.692(1.371–2.087) Non-obese hyperuricemia 2.559(1.870–3.503)
Liang J, et al. (2015), Eur Rev Med OR for NAFLD+: Uric Acid <3.7 OR 1, 3.7–<4.49 OR 1.53(1.17–1.99), P<0.001
Pharmacol Sci 4.49–<5.24 OR 2.22(1.71–2.89), 5.24–<6.11 OR 2.64(2.02–3.44), ≥6.11 OR
3.71(2.83–4.88)
Ryu S, et al. (2011), Metabolism Hyperuricemia (>7.0mg/dL males only) OR 1.21(1.07–1.38) for NAFLD= P=0.004
Sartorio A, et al. (2007), European Journal NAFLD 6.6 ± 1.7 vs non-NAFLD 5.9 ± 1.6 P<0.0001
of Clinical Nutrition
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Sullivan JS, et al. (2015), Pediatr Obes NAFLD 7.5 ± 1.4 vs obese non-NAFLD 6.1 ± 1.6* vs lean non-NAFLD 4.5 *P=0.04
± 1.6# #P=0.0007
Li Y, Xu C, Yu C, Xu L, & Miao M (2009), NAFLD 6.2 ± 1.5 vs non-NAFLD 5.4 ± 1.4 P<0.001
Journal of Hepatology
+
Model adjusted for sex, age, BMI, Systolic Blood Pressure, Diastolic Blood Pressure, total cholesterol, HDL, LDL, log of triglycerides, Log AST,
Log ALT.
=
Model adjusted for age, BMI, smoking, alcohol intake, exercise, total cholesterol, HDL, triglycerides, glucose, systolic blood pressure, insulin,
hsCRP, and presence of metabolic syndrome
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Table 2
Studies comparing fructose compared to glucose or other isocaloric intake on NAFLD, Insulin Resistance and Lipids
Study Corhort Intervention NAFLD Measurement Liver Enzymes Insulin Resistance Lipids
Jensen et al.
Maersk M, et 47 overweight 1L/d SSB (10), isocaloric milk 132–143% increase in liver fat NA NA NA
al., 2012(54) nondiabetic patients (12), diet cola (12), and water over other beverages
(30 female) (13) for 6 months
Johnson RD, Et 32 centrally Overfeeding fructose (25%) No difference No Difference No difference HOMA-IR No difference in
al., 2013(161) overweight males (n=15) vs glucose (25%) (n=17) 2 triglycerides
age 18–50. weeks
Aeberli I, et al., 9 healthy normal 3 weeks crossover of medium NA NA Decreased hepatic insulin Increased total
2013.(162) weight males age fructose (40 g/d) (MF), and high sensitivity in HF compared to HG cholesterol and LDL in
21–25. fructose (HF), high glucose (HG), MF, HF, and HS, but
and high sucrose (HS) beverage at not HG. Free fatty
(80 g/d) acids only elevated in
MF.
LeCoultre V, et 55 normal weight 6–7 days on weight maintenance Higher intrahepatic fat in 3g/kg/d NA 4g/kg/d Fructose and 3g/kg/d of NA
al. 2013 (163) males (mean age diet followed by 6–7 day and 4g/kg/d fructose, 3g/kg/day Glucose increased hepatic glucose
22.5) 1.5g/kg/d (n=7), 3g/kg/d (n=17), glucose, and saturated fat production. 4g/kg/d and 3g/kg/d
or 4g/kg/d fructose, 3g/kg/d compared to baseline, with Fructose decreased hepatic insulin
glucose (n=11) or 30% saturated tendency for higher levels in sensitivity
fats overfeed. fructose diets
Silbernagel G, et 20 healthy normal 4 week over feeding with 150g No difference No difference No difference Increased triglycerides
al., 2011. (164) weight (mean age fructose or glucose in fructose compared
30.5) (12 males, 8 to glucose
females
Stanhope K, et 32 patients (age 42– 10 week trial with 25% glucose Not assessed though visceral NA Fasting insulin, glucose, and Increased fasting
al. 2009. (65) 71) Overweight or vs 25% fructose added to diet; 2 adipose tissue, a marker for liver decreased insulin sensitivity in triglycerides in
obese (25–35 weeks inpatient energy balanced fat, was significantly higher in fructose diet, but not glucose diet glucose, not fructose,
kg/m2) (16 female) diet, followed by 8 week ad fructose, but not glucose diet but higher post
libitum diet prandial triglycerides
as well as fasting

apoB, LDL, and
oxidized LDL in
fructose diet only
Schwarz JM, et 8 healthy males (age Cross over 9 day study on Significant increase in liver fat by NA Higher endogenous glucose Increased de novo
al., 2015 (165) 18–65) with BMI isocaloric weight maintaining diet 137% in fructose diet compared to production during lipogenesis in high
<30kg/m2 of either 25% fructose or fructose complex carbohydrate diet hyperinsulinemia in high fructose fructose as compared
portion substituted with complex vs complex carbohydrate diet to complex
carbohydrates carbohydrate diet
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Fructose and Sugar: A Major Mediator of Nonalcoholic Fatty

1Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado

Pliny the Elder (The Natural History 1ST Century AD,

J Hepatol. Author manuscript; available in PMC 2018 May 01.

The Discovery of NAFLD and Its Association with Metabolic Syndrome

reactive protein), and microalbuminuria.

J Hepatol. Author manuscript; available in PMC 2018 May 01.

J Hepatol. Author manuscript; available in PMC 2018 May 01.

Fructose Effect on Lipogenesis and Fat Oxidation

Differences in Fructose and Glucose Metabolism

The principal isoform of fructokinase in the liver is fructokinase C, which phosphorylates

J Hepatol. Author manuscript; available in PMC 2018 May 01.

also occurs following fructose ingestion (80–82).

Fructokinase, the Principal Enzyme Driving Fructose-Induced Fatty Liver

Gut Permeability and the Microbiome

J Hepatol. Author manuscript; available in PMC 2018 May 01.

Role of the Immune System

Uric acid and its Role in Fructose-Mediated NAFLD

Additional studies identified potential mechanisms by which fructose-induced rise in uric

J Hepatol. Author manuscript; available in PMC 2018 May 01.

stimulation of ChREBP results in the stimulation of glucose-6-phosphatase that may mediate

some of the gluconeogenic effects of fructose (112).

Clinical Studies—Epidemiological studies have also linked hyperuricemia with NAFLD

J Hepatol. Author manuscript; available in PMC 2018 May 01.

One small randomized controlled study evaluated patients with ultrasound-diagnosed

to be a synergistic effect on inducing liver injury (134).

J Hepatol. Author manuscript; available in PMC 2018 May 01.

other genes such as transmembrane 6 superfamily member 2 (TM6SF2) which regulates

Protective Factors for Fructose-Induced NAFLD

lipogenesis (64). Further studies investigating this pathway are needed.

Other Amplifying Mechanisms

J Hepatol. Author manuscript; available in PMC 2018 May 01.

J Hepatol. Author manuscript; available in PMC 2018 May 01.

NAFLD Nonalcoholic Fatty Liver Disease

NASH Nonalcoholic steatohepatitis

HFCS high fructose corn syrup

NHANES National Health and Nutrition Examination Survey

US FLI United States Fatty Liver Index

FAS fatty acid synthase

AMPD AMP-activated protein kinase, AMP Deaminase 2

NLRP3 NOD-like receptor family pyrin domain containing 3

SDH sorbitol dehydrogenase

PNPLA3 patatin-like phospholipase domain-containing protein 3

TM6SF2 transmembrane 6 superfamily member 2

GCKR Glucokinase Regulatory Gene

in the rat. Nutr Metab. 1970; 12(4):193–219. [PubMed: 5494658]

J Hepatol. Author manuscript; available in PMC 2018 May 01.

alcoholic liver diseases. Z Gastroenterol. 1983; 21(11):651–9. [PubMed: 6659631]

J Hepatol. Author manuscript; available in PMC 2018 May 01.

31. Ackerman Z, Oron-Herman M, Grozovski M, Rosenthal T, Pappo O, Link G, et al. Fructose-

Hypertension. 2005; 45(5):1012–8. [PubMed: 15824194]

J Hepatol. Author manuscript; available in PMC 2018 May 01.

individuals with type 2 diabetes. Hepatology. 2012; 56(3):952–60. [PubMed: 22467259]

mo randomized intervention study. Am J Clin Nutr. 2012; 95(2):283–9. [PubMed: 22205311]

Gastroenterol. 2006; 6:33. [PubMed: 17081293]

J Hepatol. Author manuscript; available in PMC 2018 May 01.

Anesthesiology. 2006; 104(6):1124–30. [PubMed: 16732081]

J Hepatol. Author manuscript; available in PMC 2018 May 01.