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The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome

April 2010
Nature Reviews Gastroenterology &#38 Hepatology 7(5):251-64

April 2010
7(5):251-64

DOI:10.1038/nrgastro.2010.41

Source
PubMed

Authors:

Jung Sub Lim

Korea Institute of Radiological & Medical Sciences

Michele Mietus-Snyder

Children's National Medical Center

Jean-Marc Schwarz

Touro University College of Osteopathic Medicine

Show all 5 authorsHide

Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide, and is commonly associated with the metabolic syndrome. Secular trends in the prevalence of these diseases may be associated with the increased fructose consumption observed in the Western diet. NAFLD is characterized by two steps of liver injury: intrahepatic lipid accumulation (hepatic steatosis), and inflammatory progression to nonalcoholic steatohepatitis (NASH) (the 'two-hit' theory). In the first 'hit', hepatic metabolism of fructose promotes de novo lipogenesis and intrahepatic lipid, inhibition of mitochondrial beta-oxidation of long-chain fatty acids, triglyceride formation and steatosis, hepatic and skeletal muscle insulin resistance, and hyperglycemia. In the second 'hit', owing to the molecular instability of its five-membered furanose ring, fructose promotes protein fructosylation and formation of reactive oxygen species (ROS), which require quenching by hepatic antioxidants. Many patients with NASH also have micronutrient deficiencies and do not have enough antioxidant capacity to prevent synthesis of ROS, resulting in necroinflammation. We postulate that excessive dietary fructose consumption may underlie the development of NAFLD and the metabolic syndrome. Furthermore, we postulate that NAFLD and alcoholic fatty liver disease share the same pathogenesis.

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NATURE REVIEWS

GASTROENTEROLOGY & HEPATOLOGY VOLUME 7

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251

Department of

Pediatrics, Korea

Cancer Center Hospital,

Gongneung-dong 215,

Nowon-gu, Seoul

139-706, Republic of

Korea (J. S. Lim).

Department of

Pediatrics, University of

California, San

Francisco,

513 Parnassus Avenue,

San Francisco,

CA 94143-0434, USA

(M. Mietus-Snyder,

A. Valente,

R. H. Lustig). College of

Osteopathic Medicine,

Touro University,

1310 Johnson Lane,

Mare Island, Vallejo,

CA 94592, USA

(J.-M. Schwarz).

Correspondence to:

R. H. Lustig

rlustig@peds.ucsf.edu

The role of fructose in the pathogenesis

of NAFLD and the metabolic syndrome

Jung Sub Lim, Michele Mietus-Snyder, Annie Valente, Jean-Marc Schwarz and Robert H. Lustig

Abstract | Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide, and is

commonly associated with the metabolic syndrome. Secular trends in the prevalence of these diseases may

be associated with the increased fructose consumption observed in the Western diet. NAFLD is characterized

by two steps of liver injury: intrahepatic lipid accumulation (hepatic steatosis), and inflammatory progression

to nonalcoholic steatohepatitis (NASH) (the ‘two-hit’ theory). In the first ‘hit’, hepatic metabolism of fructose

promotes de novo lipogenesis and intrahepatic lipid, inhibition of mitochondrial β-oxidation of long-chain fatty

acids, triglyceride formation and steatosis, hepatic and skeletal muscle insulin resistance, and hyperglycemia.

In the second ‘hit’, owing to the molecular instability of its five-membered furanose ring, fructose promotes

protein fructosylation and formation of reactive oxygen species (ROS), which require quenching by hepatic

antioxidants. Many patients with NASH also have micronutrient deficiencies and do not have enough

antioxidant capacity to prevent synthesis of ROS, resulting in necroinflammation. We postulate that excessive

dietary fructose consumption may underlie the development of NAFLD and the metabolic syndrome.

Furthermore, we postulate that NAFLD and alcoholic fatty liver disease share the same pathogenesis.

Lim, J. S. et al. Nat. Rev. Gastroenterol. Hepatol. 7, 251–264 (2010); published online 6 April 2010; doi:10.1038/nrgastro.2010.41

Introduction

Nonalcoholic fatty liver disease (NAFLD) consists of a

benign form—hepatic steatosis (defined by the presence

of lipid droplets within hepatocytes on histopathologic

examination)—and the more perilous nonalcoholic

steato hepatitis (NASH), which may result in cirrhosis and

hepatic failure. NAFLD is currently the most common

liver disease worldwide, both in adults and children.1

Considering that NAFLD was first reported in adults

in 1980,2 and in children in 1983,3 the secular trend of

NAFLD prevalence is both astounding and alarming. In

the past 30 years, the prevalence and severity of NAFLD

has paralleled that of obesity, type 2 diabetes mellitus

(T2DM) and the metabolic syndrome, and a mech-

anistic association between NAFLD and these disorders

has been proposed.4 Despite concerted research into the

etiology and pathogenesis of NAFLD, the causes of

the disease remain unknown. Understanding the pathol-

ogy of NAFLD and other chronic metabolic diseases,

and how they relate to environmental changes that have

occurred in the past 30 years is essential to preventing

and treating NAFLD and the metabolic syndrome in

the future.

NAFLD and the metabolic syndrome

NAFLD is a condition of aberrant lipid storage in

hepatocytes.5 Although intrahepatic lipid accumulation

is related to lipid accumulation in adipocytes (that is,

obesity),6,7 not all intrahepatic lipid accumulation can

be explained by obesity alone. For instance, patients

with lipodystrophy are not obese, but have high levels of

intrahepatic lipid.8 Intrahepatic lipid accumulation is, in

fact, independent of BMI,9 but more accurately reflects

the existence of metabolic complications.10 The preva-

lence of the metabolic syndrome is 34% in American

adults overall, but 53% in patients with hepatic steato-

sis, and even higher (88%) in those with NASH.11 The

prevalence of both the metabolic syndrome and NAFLD

increases with age and with BMI; at autopsy, intra-

hepatic lipid is identified in 36% of lean adults and 72%

of adults with obesity,6 versus 5% of normal weight chil-

dren, 16% of overweight children, and 38% of children

with obesity.12

Patients with NAFLD are more likely to have dys-

lipidemia and increased blood pressure than individuals

of a similar weight without NAFLD.13,14 Furthermore,

the degree of intrahepatic lipid predicts metabolic dys-

function even better than does the degree of visceral

adipose tissue,15 and hepatic steatosis may precede the

onset of the metabolic syndrome and its complications.16

NAFLD more accurately predicts the existence of insulin

resistance than do the ATP III criteria, which were devel-

oped to diagnose the metabolic syndrome.17 In children18

and in adults,19 alanine aminotransferase (ALT) corre-

lates with both intrahepatic lipid, insulin resistance, and

other components of the metabolic syndrome.18 The

congruence of NAFLD and other manifesta tions of

the metabolic syndrome have led the Japanese govern-

ment to include a threshold level of ALT as part of their

definition of the metabolic syndrome.20

Competing interests

The authors declare no competing interests.

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Risk factors for NAFLD

Genetic risk factors

In a study of the correlation of ALT with the metabolic

syndrome, elevated levels of this enzyme were posi-

tively correlated with elevated serum lipid and glucose

concentra tions, blood pressure, and waist circumference

in most geographic regions except Asia,21 suggesting the

existence of hereditary modulators and/or alternate

pathogeneses of NAFLD in specific populations. NAFLD

affects specific racial and/or ethnic groups prefer entially22

and efforts have been made to find specific genetic pre-

dispositions for developing the disease. An associa-

tion between the presence of the rs738409 allele of the

patatin-like phospholipase domain-containing protein 3

(PNPLA3), which encodes a protein under metabolic

control, and intrahepatic lipid has been documented.

This allele is particularly frequent in Latino individuals,

who have the highest prevalence of NAFLD in the USA.22

Another allele in the same gene is associated with low

hepatic fat content in African Americans, who have the

lowest risk of developing NAFLD. The role of PNPLA3 in

lipid processing is not known, but this protein may also

affect other ectopic lipid depots, as visceral adipose tissue

is related to intrahepatic lipid accumulation, irrespective

of race or ethnicity.23

Metabolic risk factors

Obesity-associated insulin resistance and subsequent

hyperinsulinemia seem to be necessary though not suffi-

cient to precipitate the development of NAFLD.24 In a

retrospective study of children with biopsy-confirmed

NASH, 75% of them had fasting hyperinsulinemia,

which predicted steatosis, inflammation and fibrosis.25

Adolescents with both obesity and NAFLD had higher

liver and skeletal muscle insulin resistance, as measured

with hyperinsulinemic–euglycemic clamp techniques,

than those who were obese without NAFLD.13 Changes

in the concentrations of adipocytokines derived from

visceral adipose tissue, including increases in leptin,

resistin, tumor necrosis factor (TNF), and interleukin 6

concentrations, and decreases in adiponectin concentra-

tions, are all associated with NAFLD and insulin resis-

tance.26 Whether these changes in cytokine levels are

markers or causes of intrahepatic lipid, or whether all of

these factors are driven by an additional, yet unidentified

cause is not clear.

In addition, hyperglycemia may also exacerbate

NAFLD. In a Japanese study, the prevalence of steatosis

Key points

Nonalcoholic fatty liver disease (NAFLD) is commonly associated with the ■

metabolic syndrome

NAFLD can progress from a benign form (hepatic steatosis) to a more extreme ■

form (nonalcoholic steatoheaptitis)

Secular trends in fructose consumption coincide with those of NAFLD and the ■

metabolic syndrome; fructose is implicated in the pathogenesis of both NAFLD

and the metabolic syndrome

Hepatic fructose metabolism is reminiscent of that of ethanol; NAFLD and ■

alcoholic fatty liver disease are similar diseases

among lean adults was 62% in those who had been newly

diagnosed as having T2DM and 43% in those with

impaired fasting glucose levels, but only 27% in indivi duals

with normal fasting glucose levels.27

Dietary risk factors

Exposure to environmental factors, especially dietary

factors, is also likely to contribute to the generation of

intrahepatic lipid.28,29 Some studies have suggested that

specific dietary fats, such as trans-unsaturated fats,

contribute to hepatic steatosis.30,31 Conversely, mono-

unsaturated lipids such as oleic acid (the primary com-

ponent of olive oil),32 linoleic acid,33 or n–3 fatty acids34

decrease accumulation of intrahepatic lipid and improve

postprandial triglyceride levels, possibly by increasing

peroxisomal activity, which reduces damage by reac-

tive oxygen species (ROS).35 Another dietary factor that

probably contributes to hepatic steatosis, and the focus

of this Review, is the monosaccharide fructose. In case-

controlled studies, sugar-sweetened beverage consump-

tion was associated with hepatic steatosis, and this

association was independent of the degree of obesity.36,37

In other case-controlled studies, total fructose consump-

tion was associated with NAFLD in general, and NASH

in particular.38,39 Micro nutrient insufficiencies associated

with the consumption of sugar-sweetened beverages40

may aggravate their toxicity in producing NAFLD.

The ‘two-hit’ theory of NAFLD

Histologically, NAFLD is similar to alcoholic fatty liver

disease (AFLD). Mechanistically, although NAFLD is

thought to represent a continuum of hepatic insult, it

is probably the result of two distinct but related ‘hits’ to

the hepatocyte.41 These two steps of hepatic injury are

similar to those that are caused by ethanol and seen

in AFLD.42 The first ‘hit’ is the development of intra-

hepatic lipid and hepatic steatosis owing to an imbal-

ance of normal hepatic lipid metabolism, which results in

either excessive lipid influx, decreased lipid clearance, or

both. At this point, steatosis is potentially reversible and

does not necessarily lead to permanent hepatic injury.43

The second, less common, but more virulent ‘hit’, which

occurs in 5% of individuals with steatosis, is a concomi-

tant inflammatory process that presumably results from

oxidative stress, lipid peroxidation and cytokine action.

The resulting lobular inflammation leads to ballooning

degeneration and perisinusoidal fibrosis, which promote

apoptosis and hepatocellular death, with resulting scar-

ring and progression to NASH.44 Approximately 25% of

patients with NASH will develop portal fibrosis, complet-

ing the process that leads to cirrhosis.45 Once inflamma-

tion has started, progression to cirrhosis may only take a

few years.46 Understanding the etiology of these two ‘hits’

is essential in the prevention and treatment of NAFLD.

The first ‘hit’: hepatic steatosis

Intrahepatic lipid accrues when the rate of hepatic lipid

influx, by fatty acid import or de novo synthesis of fatty

acids, exceeds the rate of hepatic lipid clearance, by

fatty acid catabolism or lipoprotein export (Figure 1).47,48

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The following five mechanisms that influence lipid influx

or clearance may lead to hepatic steatosis.

Increased ingestion of dietary fat

The role of dietary fat in the pathogenesis of NAFLD

remains controversial. Ad lib high-fat liquid feeding to

rats generates intrahepatic lipid,49 whereas ad lib feeding

of lipid-rich chow does not.50 In humans, ingestion of

dietary fat influences the accumulation of intrahepatic

lipid,51 but stable isotope studies have demonstrated

that up to only 15% of intrahepatic lipid is derived from

dietary fat.52 Lastly, low-carbohydrate diets, which are

otherwise rich in protein and fat, are frequently used as

treatment for NAFLD.53

Increased influx of free fatty acids

Free fatty acids that result from lipolysis of subcutaneous

or visceral adipose tissue depots circulate to the liver,

and may contribute to intrahepatic lipid accumula-

tion.54,55 For instance, in T2DM complicated by obesity

and chronic inflammation, overexpression of adipose

tissue cytokines can foment insulin resistance in the liver

and adipose tissue, in part by serine phosphorylation of

insulin receptor substrate 1 (IRS-1). Insulin resistance in

adipocytes leads to failure of insulin-mediated suppres-

sion of hormone- sensitive lipase (HSL) and release of

free fatty acids from adipose tissue (especially visceral

adipose) into the circulation.56 Release of free fatty acids

from visceral adipose tissue is particularly problem-

atic, as their first circulatory pass is through the liver.

Inflammation also increases TNF-mediated upregula-

tion of hepatic fatty acid translocase,57 which, coupled

with increased influx of free fatty acids, leads to steato-

sis.58 Other conditions characterized by increased lipo-

lysis and insulin resistance, however, do not necessarily

result in steatosis. For instance, patients with poorly con-

trolled type 1 diabetes mellitus have increased lipolysis

and insulin resistance, but have minimal intrahepatic

lipid accumulation,59 presumably because of enhanced

β-oxidation of fatty acids to ketones, which accelerates

hepatic lipid clearance for energy usage by the rest of

the body.

Increased de novo lipogenesis

De novo lipogenesis is accentuated more by excess

dietary carbohydrate than by excess dietary fat.60 For

example, when total energy intake from carbohydrate

exceeds total energy expenditure, hepatic de novo

lipogenesis is increased 10-fold.61 Similarly, the rate of

de novo lipo genesis associated with a high-carbohydrate

diet is 27-fold greater than that associated with a low-

carbohydrate diet in the fasting state, and fourfold greater

in the fed state.62

For example, patients with kwashiorkor (protein mal-

nutrition despite adequate caloric intake) who are fed

a maize diet, rich in carbohydrate,63 manifest severe

hepatic steatosis, more so than patients with other

malnutrition syndromes.64

Excess accumulation of metabolites generated by

de novo lipogenesis is seen in human and rat models

of hepatic steatosis.65,66 For instance, labeled isotope

studies in individuals with obesity and steatosis have

shown that 26.1% of the intrahepatic lipid pool is gen-

erated by de novo lipogenesis.52 On a typical high-fat

diet, lean individuals exhibited less than 3% (1–2 g per

day) of carbo hydrate converted to free fatty acids by

de novo lipogenesis,67,68 but this percentage was >10% in

indivi duals with obesity and insulin resistance.69

Impaired hepatic β-oxidation of fatty acids

β-Oxidation, (the sequential removal of two-carbon

fragments for ketone production or energy genera-

tion within mitochondria) is the main route for the

metabolism of long-chain fatty acids under normal

physiological conditions.70 This process is accomp-

lished by mitochondrial trifunctional protein, which

catalyzes three separate reactions to liberate these two-

carbon fragments from acyl-CoA, shortening them in

the process. This process, however, may be disrupted

at several key enzymatic stages. Dysfunction of this

protein may cause abrupt and massive hepatic failure

with steatosis,71 similar to the pathophysiology and

liver pathology in patients with Reye syndrome.72 The

transesterification and import of fatty acids into

the mitochondrial matrix for the process of β-oxidation

is achieved through covalent binding to carnitine, a

mitochondrial carrier molecule. Each fatty acid that is

transported requires the cleavage of the carnitine–fatty

acid complex, mediated by the enzyme carnitine

O-palmitoyltransferase 1 (CPT1). Regeneration of carni-

tine by CPT1 is the key rate-limiting and regulatory step

in the process of β-oxidation. Malonyl-CoA, formed by

dimerization and subsequent decarboxylation of acetyl-

CoA (the first step in fatty acid synthesis) is also a steric

Lipoprotein-

triglyceride

LDL receptor

Lipolysis

(T2DM, insulin

resistance)

De novo

lipogenesis

Reye

syndrome

Intrahepatic lipid

Lipid input Lipid output

VLDL-

triglyceride

Decreased VLDL

synthesis,

assembly,

secretion

Hypobetalipoproteinemia

β-oxidation

CO2

Ketones

Fructose

Carbohydrate

(Kwashiorkor)

Malonyl-CoA

Figure 1 | Pathways of hepatic lipid metabolism. Three main pathways contribute to

production of intrahepatic lipid (lipid input): import of lipoprotein triglyceride by the

LDL receptor; lipolysis, which is the source of free fatty acids that are imported

into the liver; and use of carbohydrate as an energy source by de novo lipogenesis.

Two pathways contribute to clearance of intrahepatic lipid (lipid output): complete

β-oxidation of intrahepatic lipid, which leads to carbon dioxide (CO2) production, or

incomplete β-oxidation, which leads to production of ketones (which are then

exported for energy use by the rest of the body); and lipid export, usually by

conjugating intrahepatic lipids with apolipoproteins to form VLDLs. Perturbation of

any of these pathways, such as in T2DM, kwashiorkor, Reye syndrome, or

hypobetalipoproteinemia, can result in accumulation of intrahepatic lipid and lead

to hepatic steatosis. Abbreviation: T2DM, type 2 diabetes mellitus.

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inhibitor of CPT1.73,74 Experimental suppression of

malonyl-CoA formation in rats counteracts the adverse

effects of NAFLD and insulin resistance.75 Malonyl-CoA

concentrations are increased when excessive citrate, the

primary substrate of de novo lipogenesis, is generated

beyond the oxidative capacity or needs of the liver; thus,

de novo lipogenesis and defective β-oxidation are linked,

and both promote intrahepatic lipid accumulation.

In lipid-engorged hepatocytes, several vicious cycles

involving TNF, ROS, peroxynitrite, and lipid peroxida-

tion products partially block the flow of electrons in

the respiratory chain. The over-reduction of upstream

respira tory chain complexes increases mitochondrial

ROS and peroxynitrite formation. Oxidative stress

increases the release of lipid peroxidation products

and cyto kines, which contribute to the development

of NASH.76 Impaired lipid β-oxidation seems to exert

only a minor influence in the development of NAFLD

in humans,77 but might arguably be enhanced in

persons with inadequate diet-derived and endogenous

anti oxidant defense mechanisms.78

Impaired triglyceride export

Hepatocytes esterify excess free fatty acids into tri-

glycerides, which are packaged with apolipoprotein

B-100 (apo B-100) by microsomal triglyceride transfer

protein (MTTP), and exported as VLDLs. VLDL pro-

duction in patients with NASH is decreased compared

with that in healthy controls,79 and this decrease could

accentuate the accumulation of triglycerides in the liver.

However, whether decreased VLDL production is a cause

or a result of NASH is not clear. Patients with hypo-

betalipoproteinemia—an autosomal recessive disease

caused by a defect in MTTP and characterized by fat

malabsorption, low plasma cholesterol levels at a young

age, and progressive neurologic degenerative disease—

have severe hepatic steatosis. Hepatic lipid export is

diminished in this condition, yet peripheral clearance

is normal, so affected individuals have markedly dimin-

ished serum triglyceride levels.80 Patients with NASH,

however, have hypertriglyceridemia due to impaired

clearance as well as defective lipid export.

Dietary factors and hepatic steatosis

Each of these five processes that control hepatic lipid

influx and/or clearance can be perturbed sufficiently

in humans to increase intrahepatic lipid and promote

hepatic steatosis, contributing to—but not fully explain-

ing—the global increase in prevalence and severity of

NAFLD. The inexorable rise in daily calorie intake seen

in the past 30 years in industrialized countries may also

have a role in this increase. In the USA, adult men have

increased caloric intake by 187 kcal per day, women

by 335 kcal per day, and adolescents of both sexes by

275 kcal per day.81 The prevalence of both NAFLD and

the metabolic syndrome have increased dramatically

worldwide with the global export of the Western diet.

Whether the excess of energy intake is the main factor

that underlies the NAFLD epidemic, whether specific

macronutrient and/or micronutrient components of the

diet are involved, or whether both factors have a role has

not been fully elucidated.

Dietary fat consumption

Despite documented increases in daily caloric intake,

total dietary fat intake has remained stable in the last

30 years (5.3 g per day decrease in men, 5 g per day

increase in women), while the percentage of calories

ingested from saturated fat has decreased.82 Although

high-fat feeding can induce overnutrition and intra-

hepatic lipid in experimental animal and human models,

it does so only with concomitant carbohydrate inges-

tion.50,51,83 Furthermore, long-term voluntary consump-

tion of an increased percentage of fat, as is seen in the

Atkins diet, did not result in increased caloric intake,

and did not increase the risk of obesity or NAFLD.84,85 In

a 2-year intervention study, participants on either the fat-

liberalized Mediterranean (monounsaturated fats) or the

Atkins (all fats) diet without imposed caloric restriction,

demonstrated comparable weight loss and decreased cir-

culating fasting insulin and triglyceride concentrations.86

Indeed, high-fat, low-carbohydrate diets seem to amelio-

rate elevated liver enzyme levels and decrease metabolic

disease risk.53 Therefore, the quantity of ingested dietary

fat does not seem to be the cause of NAFLD, although

qualitative fat composition may be of concern.

Trans-unsaturated fat consumption

With the advent of Crisco, the first commercial trans-

unsaturated or ‘partially hydrogenated’ fat, in 1911,

various processed food products, especially margarines

and baked goods, have included trans-unsaturated fat in

order to improve shelf life. Due to the trans- isomerization

of the double bond in these fatty acids, bacteria cannot

digest them, which prevents food from becoming rancid.

Unfortunately, our mitochondria (derived evolutionarily

from bacteria) also cannot digest trans-unsaturated

fats, which, therefore, do not undergo mitochondrial

β-oxidation,87 and increase the risk of hepatic steatosis.

Experimental feeding of trans-unsaturated fats (termed

the ‘Western Lifestyle Diet’) to animals is associated with

rapid accumulation of intrahepatic lipid.31 Consumption

of trans-unsaturated fats peaked in the 1960s, but since

1988, owing to the recognized association of trans-

unsaturated fat with cardiovascular disease, the percent-

age of calories from trans-unsaturated fat consumed in

the Western diet has been gradually decreasing. A reduc-

tion from 3.0% in 1982 to 2.2% in 2002 in total energy

derived from trans-unsaturated fats was documented in

the Minnesota Heart Survey.88 Thus, while consumption

of trans-unsaturated fats could mechanistically underlie

the development of NAFLD and the metabolic syndrome,

consumption trends are temporally disparate with the

current epidemic of these diseases.

Carbohydrate consumption

When it comes to which macronutrient promotes intra-

hepatic lipid, who knows better than the French? In

recog nition that dietary carbohydrate is more steato-

genic than fat, the prototypical fatty liver, ‘paté de foie

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gras’, is made by force-feeding ducks or geese with a diet

of maize (corn), wheat, and soya cake—a macro nutrient

breakdown that favors carbohydrate (47.9%) over fat

(2.1%).89 In contrast to the results of dietary fat intake,

carbohydrate overfeeding in humans results in exces-

sive weight gain and hepatic steatosis in a short period of

time. For example, in the ‘Guru Walla’ overfeeding para-

digm, consumption of a diet of 7,000 kcal per day that

consists of 70% carbohydrate and 15% fat, and is mainly

composed by sorghum (a kind of maize), leads to hepatic

steatosis within a few weeks.90 Food consumption survey

data from the US Department of Agriculture, reported by

the National Health and Nutrition Examination Survey

program between 1971 and 2004, also indicate that the

observed increase in total energy intake in the US popula-

tion is accounted for almost completely by carbo hydrate

consumption, with a 67.7 g increase per day in men and

a 62.4 g increase per day in women within that time

frame.82 An excess in dietary carbohydrate consumption

has been reported specifically in patients with NASH.91

Secular trends in fructose intake

The predominant carbohydrate responsible for the rise in

caloric consumption associated with the typical Western

diet is the monosaccharide fructose, which is consumed

either as sucrose (50% fructose) or as high-fructose corn

syrup (42% or 55% fructose). Before 1900, US Americans

consumed approximately 15 g of fructose per day (4%

of total calories), mainly through fruits and vegetables.

Before World War II, fructose intake had increased to

24 g per day (5% of total calories); by 1977, it was 37 g

per day (7% of total calories); and by 1994, 55 g per day

(10% of total calories). Adolescents today consume over

72.8 g per day (12.1% of total calories) of fructose;92

20% of teenagers consume 25% or more of their total

calories as fructose.93 Thus, fructose consumption has

increased fivefold over the last century and more than

doubled in the last 30 years. Food disappearance data

from the Economic Research Service (ERS) of the US

Department of Agriculture support this secular trend.

Although the ERS documents partially decreased sucrose

intake per capita, the total annual consumption of caloric

sweeteners per capita has increased from 33 kg to 43 kg

in 30 years.94 Although the presence of high-fructose

corn syrup in soft drinks has received most of the atten-

tion,95,96 high fruit juice intake has also been associated

with childhood obesity.97 Currently, Americans consume

sugar at a rate of 66.8 kg per year (180 g per day), half of

which is fructose.

Fructose and the metabolic syndrome

Many investigators have implicated fructose in the

pathogenesis of the metabolic syndrome40,98–105 and

NAFLD.39,106,107 The liver is the principal site of fructose

metabolism, as it possesses the fructose-specific Glut5

transporter.108 Although adipo cytes possess GLUT-5

mRNA and protein, the level of this transporter in adipose

tissue is quite low.109 The kidney and small intestine also

possess GLUT-5 transporters, but their function is to

transport fructose molecules across their lumena, either

for urinary excretion (to eliminate any systemic fructose

that escapes hepatic clearance) or for release into the

portal circulation, which passes directly to the liver. The

hepatic metabolism of fructose is very different to that

of glucose in that it is insulin independent, bypasses the

process of glycolysis, and increases de novo lipo genesis

to a greater extent. Indeed, the hepatic metabolism of

fructose is more reminiscent of that of ethanol.110 Similar

to ethanol, fructose can induce each of the phenomena

associated with the metabolic syndrome (Figure 2).

Hypertension

Fructose is phosphorylated by fructokinase, which uses

ATP as the phosphate donor, depleting the hepatocyte of

intracellular ATP. The scavenger enzyme AMP deami-

nase 1 reclaims additional phosphates from ADP, and

in the process generates the waste product uric acid.

Uric acid acts within vascular smooth muscle to inhibit

endothelial nitric oxide synthase and resultant nitric

oxide production, which promotes hypertension.100

Our group has shown that sugar-sweetened beverage

consump tion positively correlates with uric acid and

blood pressure levels in children,111 while others have

documented this association in adults.112 Furthermore,

the uric acid inhibitor allopurinol can reduce blood

pressure in adolescents113 and adults with obesity.114

Hepatic steatosis

Owing to the excess substrate load, excess mitochondrial

acetyl-CoA is formed, exceeding the ability of the tri-

carboxylic acid (TCA) cycle to metabolize it. The excess

acetyl-CoA is converted to citrate, exits into the cytosol via

the citrate shuttle, and serves as the substrate for de novo

lipogenesis. Acetyl-CoA dimerizes and is decarboxy-

lated to form malonyl-CoA, which inhibits mitochon-

drial β-oxidation. Triglycerides newly formed by de novo

lipogenesis115 can overwhelm the lipid export machin-

ery and precipitate in the liver, forming intra hepatic

lipid and leading to hepatic steatosis.

Hepatic insulin resistance

Fructose-1-phosphate activates dual-specificity mitogen-

activated protein kinase kinase 7 (MKK7),116 which

stimulates the hepatic enzyme mitogen-activated protein

kinase 8 (MAPK8).117 This kinase is thought to be the

bridge between hepatic metabolism and inflamma-

tion.118 Furthermore, the intermediate diacylglycerol,

which accumulates during de novo lipogenesis acti-

vates hepatic protein kinase C ε type (PKCε).119 Both

MAPK8 and PKCε trigger serine phosphorylation and

subsequent inactivation of IRS-1, which leads to hepatic

insulin resistance.120–123

Dyslipidemia and muscle insulin resistance

Free fatty acids are also formed, which, when packaged as

triglycerides into heavily fat-laden VLDLs, are cleared with

low efficiency, causing dyslipidemia and augmenting the

risk of cardiovascular disease.115,124 Excess circulating lipid

is also taken up by skeletal muscle to form intra myocellular

lipid, which leads to muscle insulin resistance.125,126

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Hyperglycemia and T2DM

Fructose, a gluconeogenic precursor, increases synthe-

sis of the forkhead box protein O1 (FOXO1).127 Hepatic

insulin resistance, made worse by elevated fructose

concentra tions, prevents the phosphorylation of FOXO1,

which allows this protein to enter the nucleus and induce

the transcription of enzymes that promote gluconeo-

genesis. Increased hepatic glucose output foments hyper-

glycemia, and is likely to contribute to the development

of T2DM.

Obesity

Fructose also contributes to increased food consump-

tion and obesity. Direct effects of fructose on the central

nervous system (CNS) include stimulation of hormones

that stimulate appetite and reward,128–130 and reduction

of hypothalamic malonyl-CoA levels, which results in

increased AMP kinase concentrations, driving further

food intake.131 Indirect effects of fructose on the CNS

include hypertriglyceridemia, which reduces leptin

transport across the blood–brain barrier,132 and hyper-

insulinemia, which blocks the leptin signal transduction

pathway, resulting in a sense of starvation, again driving

further food intake.133

Endotoxinemia

Fructose consumption may also contribute to bacterial

overgrowth and increased intestinal permeability.39,105

Animal and human studies suggest that NAFLD is associ-

ated with small intestinal bacterial overgrowth,134 which

NO

Dyslipidemia

LPL

Leptin

resistance

Free fatty acids

Muscle

insulin

resistance

Triglycerides

Insulin

Uric acidIMP

PyruvatePyruvate

Liver

Mitochondria

Fructose-1,6-bis-P

Fructose-6-P

Glyceraldehyde

Dihydroxyacetone-P

PP2A

Xylulose-5-P

PGC-1β

PFK

Citrate

Fructose-1-P

Fructokinase ADP AMP

ATP

Pi

Blood pressure

Inammation

Hyperglycemia

Hepatic insulin

resistance

Glucose

Gluconeogenesis

Fructose

GLUT-5

MKK7

MAPK8

DAG

Lipid

droplet

pSer-IRS-1

IRS-1

PKCε

ACLACC1 FAS

TCA

cycle

ATP+

CO2

Acetyl-CoA

Acetyl-CoA Acyl-CoA VLDL

ApoB

MTTP

Malonyl-CoA

CPT-1

Citrate

ChREBP

AMP deaminase 1

Obesity

FOXO1

SREBP1c

Figure 2 | Hepatic fructose metabolism. Fructose induces: substrate-dependent phosphate depletion, which increases uric

acid and contributes to hypertension through inhibition of endothelial nitric oxide synthase and reduction of NO (green);

excess formation of citrate, which serves as the substrate for de novo lipogenesis (orange); excess formation of malonyl-

CoA, which inhibits β-oxidation (red); hepatic lipid droplet formation and steatosis; activation of MAPK8 and PKCε, which

contributes to serine phosphor ylation of IRS-1 and hepatic insulin resistance, which in turn promotes hyperinsulinemia and

influences substrate deposition into fat (yellow); export of free fatty acids, which leads to VLDL formation and muscle

insulin resistance (light blue); increased synthesis of FOXO1, which promotes gluconeogenesis and hyperglycemia (pink);

and central nervous system hyperinsulinemia, which antagonizes central leptin signaling and promotes continued energy

intake. Abbreviations: ACL, ATP-citrate lyase; ACC1, acetyl-CoA carboxylase 1; apo B, apolipoprotein B-100; ChREBP,

carbohydrate response element binding protein; CPT-1, carnitine O-palmitoyl transferase 1; FAS, fatty acid synthase; DAG,

diacylglycerol; FOXO1, forkhead box protein O1; GLUT-5, solute carrier family 2, facilitated glucose transporter member 5;

IRS-1, insulin receptor substrate 1; LPL, lipoprotein lipase; MAPK8, mitogen-activated protein kinase 8; MKK7, mitogen-

activated protein kinase kinase 7; MTTP, microsomal triglyceride transfer protein; NO, nitric oxide; PFK,

6-phosphofructokinase; PGC-1β, peroxisome proliferator-activated receptor γ coactivator 1β; Pi, inorganic phosphate; PKCε,

protein kinase C ε type; PP2A, protein phosphatase 2a; pSer-IRS-1, serine phosphorylated IRS-1; SREBP-1c, sterol

regulatory element binding protein-1c; TCA, tricarboxylic acid.

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is linked to circulating endotoxinemia and inflamma-

tory cytokines. The presence of these factors in the

blood has also been reported in patients with AFLD.135

Translocation of bacterial endotoxins through a leaky

gut lumen to the portal blood increases the exposure of

the liver to inflammation and injury. The gut microflora,

therefore, may be a key link between fructose feeding,

plasma endotoxin levels, and systemic and hepatic

inflammation associated with the metabolic syndrome.

Similarities between fructose and ethanol

Promotion of de novo lipogenesis

In contrast to the hepatic conversion of glucose pri-

marily to glycogen, a fructose bolus is metabolized by

glyco lysis directly to pyruvate (Figure 2). This process is

accentuated in individuals with insulin resistance and/or

obesity.52,69,136 Thus, in response to a fructose bolus, a large

volume of acetyl-CoA is generated to enter the hepatic

mitochondrial TCA cycle. This cycle, however, has a rela-

tively fixed maximum velocity to deal with its substrate,

modifiable by exercise, cold, altitude, and concentrations

of thyroid hormone. When the liver mitochondria are

not able to metabolize the entire fructose- derived acetyl-

CoA substrate excess, any extra exits the mitochondria

into the cytosol in the form of citrate via the citrate

shuttle.137 In the cytosol, carbohydrate response element

binding protein (ChREBP) activates the enzymes respon-

sible for de novo lipo genesis,138,139 which transforms

the citrate, through malonyl-CoA, to generate fatty

acyl-CoA. Furthermore, fructose-1-P stimulates per-

oxisome proliferator- activated receptor γ coactivator 1β

(PGC-1β), a trans criptional co-activator for sterol regu-

latory element binding protein 1c (SREBP-1c). SREBP-1c

further increases the activity of the enzymes involved in

de novo lipogenesis, which leads to the generation of even

more fatty acyl-CoA.140 The majority of the fatty acyl-

CoA is packaged into VLDL for export, but a proportion

accumulates instead as lipid droplets in the hepatocyte.29

This double activation of de novo lipogenesis, mediated

through both the carbo hydrate (ChREBP) and lipogenic

(SREBP-1c) transcription factor pathways, seems to be

exclusive to fructose, and probably explains its ability to

generate intrahepatic lipid very rapidly, as it relies upon

a substrate-driven effect that does not need insulin

stimula tion. Qualitatively and quantitatively, the genera-

tion of acetyl-CoA, increased de novo lipo genesis,141 and

increased intrahepatic lipid formation142 that result from

excessive fructose intake are similar to those seen with

ethanol consumption.

Inhibition of β-oxidation

Fructose increases the intracytosolic citrate available for

de novo lipogenesis. The process of de novo lipogenesis

involves three enzymes: ATP-citrate lyase, which recon-

verts citrate to acetyl-CoA; acetyl-CoA carboxylase 1

(ACC1), which dimerizes and decarboxylates acetyl-

CoA into malonyl-CoA; and fatty acid synthase, which

adds further two-carbon fragments to malonyl-CoA to

elongate it to form fatty acyl-CoA. These two-carbon

fragments are generated in the mitochondria, after

regeneration of carnitine by CPT1 after transesterifica-

tion and import of fatty acids into the mitochondrial

matrix. Malonyl-CoA, which is generated by de novo

lipogenesis from carbohydrate, inhibits CPT174 and pre-

vents β-oxidation,143 which contributes to intrahepatic

lipid accumulation. In animal models, defective fatty

acid oxidation and hepatic insulin resistance result in

steatosis.144 These same phenomena occur in animals

when ethanol is the energy substrate.145,146 In ethanol-

fed rodents, β-oxidation is blocked by increased activity

of ACC1, which leads to increased levels of malonyl-CoA

and decreased activity of CPT1.147

Suppression of hepatic lipid export

The principal exit strategy of intrahepatic lipid is its

export from the liver as VLDL. The synthesis of VLDL

depends on MTTP for transfer of lipids to the apo B-100

protein, which is necessary for its correct folding before

export. Peroxisome proliferator-activated receptor α

(PPARα) regulates mitochondrial and peroxisomal fatty

acid oxida tion, and stimulates hepatic MTTP expression,

coordinating energy stores and facilitating the normal

excretion of hepatic lipid for peripheral processing.148

Both fructose149 and ethanol148,150 reduce hepatic PPARα

activity, which results in downregulation of MTTP.151

Hepatic tri glyceride availability is the major determi-

nant of VLDL secretion rate, but MTTP activity seems

to determine VLDL size, which determines the rate of

clearance of these molecules in the plasma.152 Elevated

circulating VLDL concentrations in a hamster model

of insulin resistance induced by high fructose feeding

was associated with VLDL over production;153,154 while

decreased clearance of tri glyceride-rich VLDL has been

demonstrated in fructose-fed rat models.151,155 Similarly,

suppression of MTTP activity by ethanol increases

VLDL production but reduces lipid export machin-

er y.156 Triglyceride-enriched VLDL levels are typically

100

Alanine aminotransferase (U/l)

Sugar-sweetened-beverage consumption (kcal per day)

African American (n

72)

0.20

0.099

White (n

118)

0.23

0.013

0 200 400 600 800 1,000 1,200 1,400

Figure 3 | Association between sugar-sweetened beverage consumption and serum

alanine aminotransferase in a population of children seeking obesity treatment at

the University of California, San Francisco.164 These two variables are more

strongly correlated in white children than in African American children.11

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elevated in patients with alcoholism.157 Treatment with

a PPARα agonist leads to upregulation of MTTP and

increased VLDL export and turnover, and alleviates

the intrahepatic lipid accumulation of both NAFLD158

and AFLD.148,150

Chronic ethanol159 and fructose160 feeding in rat and

hamster models respectively, are also associated with

increased intestinal delivery of apolipoprotein B-48

(apo B-48). Apo B-48 is a protein unique to chylo microns.

It is only generated in the small intestine, where an alter-

natively spliced stop codon truncates the apo B-100

mRNA transcript. Chylomicrons containing apo B-48

delivered to the liver are metabolized into triglyceride-

rich remnant lipoproteins that, unlike VLDLs (which

contain apo B-100) and their LDL metabolites, cannot

be cleared by the LDL cell-surface receptor that mediates

endo cytosis of cholesterol- rich apo-B-100-containing

lipoproteins in all nucleated cells. This process contrib-

utes to enhanced circulation time of triglyceride-rich

proteins, hyper triglyceridemia, and atherogenicity.

While the specific role of fructose or ethanol in human

apo B-48 synthesis has not been examined, increased

production of intestinally derived particles containing

apo B-48 occurs in humans with hyperinsulinemia and

insulin resistance.161

Intrahepatic lipid accumulation

In mouse models, fructose overfeeding results in rapid

development of intrahepatic lipid, hyper triglyceridemia,

and insulin resistance.162,163 Our group has shown similar

correlative and causative phenomena in humans.

Analysis of data from the Weight Assessment for Teen

and Child Health (WATCH) Clinic at the University of

California, San Francisco, demonstrated that daily sugar-

sweetened beverage consumption assessed by recall

(in kcal per day) correlated with ALT concentrations in

white children, although this correlation was smaller

in African American children164 perhaps owing to genetic

differences in modulators of lipid metabolism, such

as PNPLA3165 or PPARα (Figure 3).166 Although ALT

concentrations are an imperfect measure of NAFLD,167

serum levels of this protein correlate, nonetheless, with

intrahepatic lipid accumulation, especially in children.168

A similar relationship between consumption of sugar-

sweetened beverages and NAFLD has also been shown

in adults.33,36 Moreover, in a crossover, isocaloric feeding

study in adults performed by our group, in which diets

rich in fructose or complex carbohydrates were com-

pared, fructose feeding increased intrahepatic lipid

accumulation by 38% within 8 days, as measured by

magnetic resonance spectroscopy.169 These results indi-

cate that, even in an isocaloric state, fructose is more

likely to overwhelm the hepatic lipoprotein packaging

machinery than other dietary factors, which results in

accumulation of intrahepatic lipid, hepatic steatosis,

and elevation of ALT. These associative and mechanistic

data from animals and humans point to excessive fruc-

tose consumption as a proximate cause of NAFLD. Once

fructose-induced obesity and insulin resistance are estab-

lished, other factors, such as adipocytokines and intesti-

nal endotoxins, may also increase intrahepatic lipid levels

and exacerbate hepatic dysfunction.

The second ‘hit’: inflammation

Fructose is different from glucose in yet another way, in

that it can promote hepatocellular damage. Molecularly,

HOH

D-Glucose

(linear form)

α-D-Glucopyranose

(Haworth projection)

CH2OH

HO HO

444

6CH2OH

HHH

HOH

D-Fructose

(linear form)

α-D-Fructofuranose

(Haworth projection)

CH2OH

HOH2C

CH2OH

HO H

Oxygen

HOH

HCC

Carbon

Hydrogen

Figure 4 | Molecular renditions of glucose and fructose. a | Glucose in the linear, chair (Haworth), and space-occupying

projections. b | Fructose in the linear, chair (Haworth), and space-occupying projections. In the linear form, both substrates

possess a reactive aldehyde or ketal moiety, which can bind nonenzymatically to freely available amino groups of proteins. At

body temperature and pH, however, the chair form of glucose predominates. This conformation is a glucopyranose

(6-membered ring), with equatorial hydroxyl groups and is molecularly stable, which limits its protein reactivity. The chair form

of fructose is a fructofuranose (5-membered ring) with two axial hydroxymethyl groups that exert allosteric and ionic forces

on the unstable furanose ring, which favors the linear form. Thus, at body temperature and pH, the majority of fructose exists

in the linear form and is more reactive to proteins than glucose.

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glucose is found in two steroisomeric forms: the linear

aldehyde form, and the gluco pyranose (6-membered

ring) form (Figure 4). The aldehyde form of glucose

is highly reactive with ε-amino groups of lysine. The

nonenzymatic exothermic reaction between these

factors leads to protein glycation,170 which is termed

the Maillard or ‘browning’ reaction; this is the reason

why bananas become brown with time. However, at

37 °C and pH 7.4, the ring form is molecularly stable

and nonreactive, owing to its 6-membered gluco-

pyranose and equatorial hydroxyl groups. In these

conditions, 80% of glucose is thought to remain in the

ring form. Fructose is also found in two stereoisomeric

forms: the linear ketal form, and the fructofuranose

(5-membered ring) form. The latter has two axial

(abutting) hydroxymethyl groups, which exert allo-

steric and ionic forces to the unstable furanose ring

and drive it toward the linear form. Thus, at body tem-

perature and pH, 80% of fructose is thought to exist

in the linear form, with a reactive ketal group. This

difference explains why nonenzymatic fructosyla-

tion is seven times more rapid than protein glyca-

tion with glucose as the substrate.171,172 Each protein

fructosylation reaction releases a superoxide radical

(Figure 5).173 Fructose generates 100 times more ROS

than glucose,174,175 which, if not quenched by an anti-

oxidant (in the case of liver, gluta thione), can promote

hepatocellular damage.

HN NH

Reduced

glutathione

Oxidized

glutathione

HOH

Fructose

CH2OH

Schiff base

CH2OH

–

HC N+

Heyns product

CH2OH

HC NH

Protein Protein

Acetaldehyde

adduct

CCH3

Acetaldehyde

CCH3

Ethanol

HO CH2CH3

NADH NAD+

Lipid

protein

Peroxidation

Cell damage

Necroinammation

Protein

ADH1B

Figure 5 | Generation of reactive oxygen species by fructose or ethanol. Fructose first forms an intermediate Schiff base

with the ε-amino group of lysine, which then spontaneously hydrogenates to form an irreversible Heyns rearrangement

product (hydroxyamide linkage or fructose adduct), through the ‘Maillard reaction’. Each protein fructosylation generates

one superoxide radical (O2

–), which must be quenched by an antioxidant, such as glutathione. Alternatively, ethanol is

metabolized by alcohol dehydrogenase 1B (ADH1B) to NADH and acetaldehyde. Acetaldehyde, through a similar Maillard

reaction, forms acetaldehyde adducts, with generation of superoxide radicals, which must also be quenched by

antioxidants. In the absence of adequate antioxidant capacity, production of reactive oxygen species leads to peroxidation,

hepatocellular damage, necroinflammation (nonalcoholic steatohepatosis), fibrosis, and ultimately cirrhosis.

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Although difficult to demonstrate in humans, this

pheno menon is easily recapitulated in vitro. In one

study in mouse lymphoma cells, fructose induced non-

enzymatic fructosylation and DNA damage, which

resulted in internucleosomal cleavage and apoptosis.176

In a study of hepato cytes in monolayer culture, incuba-

tion with fructose yielded no direct damage.177 However,

when these hepatocytes were preincubated with sub-

lethal doses of hydrogen peroxide, their ROS-quenching

ability was extinguished. Incubation with fructose was

as toxic as that with other organic aldehydes and caused

hepatocellular death. These experiments suggest that in

a susceptible redox environment fructose can act as a

direct hepatotoxin.

A similar phenomenon was also demonstrated

in vivo. The methionine-choline-deficient diet in rats

generates hepatic steatosis and NASH within 3 weeks.178

Methionine is the source of the methyl group for gluta-

thione synthesis, and choline is a building block of

phosphatidyl choline, a required component of VLDL

particle assembly.179 Deficiency in methionine and

choline promotes intrahepatic lipid accumulation

and ROS-mediated damage. Interestingly, if the energy

substrate for the methionine-choline-deficient diet is

starch (glucose), no intrahepatic lipid formation or

hepato celluar death ensues; however, if the substrate

is sucrose (glucose plus fructose), the liver undergoes

massive steato sis, apoptosis, necrosis, and fibrosis.180

These data suggest that large volumes of fructose, in

combination with micronutrient insufficiencies, can

impair glutathione and possibly other hepatic anti-

oxidant reserves,181 contributing to the second ‘hit’ of

hepatic damage in NAFLD, and the evolution of hepatic

steatosis to NASH. Although not yet demonstrated in

humans, this hypothesis is particularly attractive, as

several studies have shown that children with obesity,

especially sugar- sweetened beverage drinkers, despite

being over nourished are also micronutrient mal-

nourished.182,183 In this sense, hepatic inflammation

caused by fructose is again reminiscent of that caused by

alcoholism, in which micronutrient deficiencies are also

commonplace.184 The hepatic conversion of ethanol to

acetaldehyde by the enzyme alcohol dehydro genase 1B,

which results in the generation of glyco aldehyde radi-

cals, is akin to the conversion of fructose to carbo-

nyl metabolites.146 Glutathione-dependent hepatic

detoxifica tion processes are impaired under condi tions

of nutritional deficiency,185 and improved with provi-

sion of nutrients that serve as methyl donors.186 In the

absence of adequate nutritional substrate, we surmise

that these toxins generate a flux of ROS that can exceed

antioxidant reserves. Hepatic ROS may be generated

through other mechanisms as well, such as oxidation

of saturated fat.187 ROS formation, either directly from

fructose, ethanol or fat, or indirectly from mitochon-

drial dysfunction caused by defective β-oxidation, is a

likely initiator of endoplasmic reticulum stress106 and

the unfolded protein response,123,188 both of which may

also contribute to the pathogenesis of NAFLD and the

metabolic syndrome.189

Conclusions

Increased consumption of fructose, and the increase

in prevalence of obesity, the metabolic syndrome and

NAFLD in adults and children show no sign of plateau.

Every country that has adopted the fructose-rich, fiber-

poor, and micronutrient-poor Western diet has suffered

the same fate.190 Recognizing the relationship between

sugar consumption, cardiovascular disease, and the

metabolic syndrome, the American Heart Association

has recom mended reduction of daily sugar intake by

more than half.191 Other associations have called for

global fructose restriction.192 Elevated levels of fructose

have important effects on hepatic biochemistry and are

associated with cellular pathology. We postulate that

fructose is a proximate cause of both of the ‘hits’

that cause hepatic damage in NAFLD, recapitulating

the toxic effects of ethanol. This similarity is not sur-

prising, as fructose and ethanol are highly congruent

evolutionarily and biochemically, and ethanol is, in fact,

produced by fermentation of fructose. The only differ-

ence is that for fructose we humans have to perform

our own glycolysis, while for ethanol, yeast perform the

glycolysis for us. Excessive intake of both of these sub-

stances leads to excessive hepatic substrate burden, an

excess of mitochondrial acetyl-CoA being transformed

into citrate and shuttled to the cytosol, stimula tion of

de novo lipo genesis, and an excess of malonyl-CoA

inhibiting hepatic lipid β-oxidation. The combina-

tion of these factors is a recipe for hepatic steatosis.

The reactive aldehyde or ketal groups in both of these

molecules can lead to ROS formation, which, when

associated with lack of antioxidant capacity aggravated

by micronutrient mal nutrition, might cause necro-

inflammation, fibrosis, and subsequent cirrhosis. Given

these similarities, NAFLD and AFLD can be viewed as

similar diseases that are driven by ostensibly different

substrates. Similarly to alcoholism, we postulate that

disease prevention by reduction of fructose consump-

tion and improved nutritional status, rather than treat-

ment of NAFLD and the metabolic syndrome, is likely

to be the only rational public health effort to combat

these diseases.

Review criteria

Using PubMed and the substrate key terms “fructose”

or “ethanol”, combined with the effector terms “de novo

lipogenesis”, “hypertriglyceridemia”, “steatosis”, “fatty

liver”, “NAFLD”, “lipoproteins”, “insulin resistance”,

“metabolic syndrome”, and “reactive oxygen species”, a

review of the literature published between the years 1966

and 2009 on hepatic ethanol and fructose metabolism,

carbohydrate–protein adduct and reactive oxygen species

formation was conducted. Mechanistic studies in

animals that addressed directionality of effect, along with

correlative or mechanistic data in humans that supported

or detracted from such mechanisms were included. After

syntheses of these data, consultations with experts

in the field of fructose metabolism and hepatic lipid

metabolism were obtained to establish veracity of

these findings.

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Acknowledgments

The authors would like to thank Drs S. Noworolski,

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R. Krauss for constructive input. Dr Schwarz’s

laboratory is supported by an NIH–National Institute

of Diabetes and Digestive and Kidney Disease grant

(R01 DK078133) and an American Diabetes

Association Clinical Research Award (1-08-CR-56).

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Genistein and Sex Hormone Supplementation Modulated Hepatic PPARα, δ, and γ Subtypes and STAT1 Expressions in a NASH Rat Model with Bilateral Orchidectomy

Article

Full-text available

Feb 2024

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatic inflammation and steatosis. Currently, limited data exist regarding the risk of NASH in transgender women and the treatment options for this particular population. The use of testosterone supplementation is unfavorable for transgender women, and estrogen supplementation is linked to an increased risk of breast cancer; thus, an isoflavone derivative compound known as “genistein” could serve as a viable substitute for a hormone supplement in this context. The purpose of this study was to investigate the treatment effects and mechanisms of actions of genistein and sex hormones in orchidectomized (ORX) rats with nonalcoholic steatohepatitis induced via a high-fat high-fructose diet (HFHF) model. Male Sprague-Dawley rats (n = 42) were randomly assigned into seven groups; control, ORX + standard diet, HFHF, ORX + HFHF, ORX + HFHF diet + testosterone (50 mg/kg body weight (BW) once weekly), ORX + HFHF diet + estradiol (1.6 mg/kg BW daily), and ORX + HFHF diet + genistein (16 mg/kg BW daily). The duration of the study was 6 weeks. Some parts of liver tissue were used for histological examination by H&E staining. The determination of fat accumulation was performed using Oil Red O staining. SREBP1c and FAS gene expression were quantified using real-time PCR technique. The levels of all types of peroxisome proliferator-activated receptors (PPARs; α, δ, γ), proteins, and signal transducer and activator of transcription 1 (STAT1) signaling pathway were determined by both immunoblotting and immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, and hepatocyte ballooning, and showed higher levels of genes related to de novo lipogenesis, including SREBP1c and FAS. The expression of PPARγ and STAT1 were upregulated, while the expression of PPARα and PPARδ were downregulated in the ORX + HFHF group. Testosterone, estradiol and genistein treatments improved NASH histopathology together with the reversal of all types of PPAR protein expressions. Interestingly, genistein decreased the levels of STAT1 protein expression more than those of testosterone and estradiol treatment. Genistein and sex hormone treatment could ameliorate NASH through the upregulation of PPARα, and PPARδ, and the suppression of PPARγ and STAT1 expression.

Genistein and sex hormone treatment alleviated hepatic fat accumulation and inflammation in orchidectomized rats with nonalcoholic steatohepatitis

Article

Full-text available

Feb 2024

Testosterone deficiency has been reported to accelerate nonalcoholic fatty liver disease (NAFLD). However, there are minimal data on the risk of NAFLD in transgender women and the treatment of NAFLD in this population. This study aimed to investigate the treatment effects and the mechanisms of action of genistein and sex hormones in orchiectomized (ORX) rats with nonalcoholic steatohepatitis (NASH) induced by a high fat high fructose diet (HFHF). Seven-week old male Sprague-Dawley rats were randomly divided into 7 groups (n = 6 each group); 1) control group, 2) ORX + standard diet group, 3) HFHF group, 4) ORX + HFHF group, 5) ORX + HFHF diet + testosterone group (50 mg/kg body weight (BW) once weekly), 6) ORX + HFHF diet + estradiol group (1.6 mg/kg BW daily), and 7) ORX + HFHF diet + genistein group (16 mg/kg BW daily). The duration of treatment was 6 weeks. Liver tissue was used for histological examination by hematoxylin and eosin staining and hepatic fat measurement by Oil Red O staining. Protein expression levels of histone deacetylase3 (HDAC3) and peroxisome proliferator-activated receptor delta (PPARδ) were analyzed by immunoblotting. Hepatic nuclear factor (NF)-ĸB expression was evaluated by immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, hepatocyte ballooning and the highest percentage of positive Oil Red O staining area among all groups. The expression of HDAC3 and PPARδ was downregulated, while NF-ĸB expression was upregulated in the ORX + HFHF group when compared with control and ORX + standard diet groups. Testosterone, estradiol and genistein treatment improved histological features of NASH together with the reversal of HDAC3, PPARδ and NF-ĸB protein expression comparing with the ORX + HFHF group. In summary, genistein and sex hormone treatment could alleviate NASH through the up-regulation of HDAC3 and PPARδ, and the suppression of NF-ĸB expression.

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May 2024

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Article

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BIOSCIENCE REP

Several models of mice-fed high-fat diets have been used to trigger non-alcoholic steatohepatitis and some chemical substances, such as carbon tetrachloride. This study aimed to evaluate the joint action of a high-fat diet and CCl4 in developing a short-term non-alcoholic steatohepatitis model. C57BL6/J mice were divided into two groups: standard diet-fed (SD), the high-fat diet-fed (HFD) and HFD + fructose-fed and carbon tetrachloride (HFD+CCl4). Animals fed with HFD+CCl4 presented increased lipid deposition compared with both SD and HFD mice. Plasma cholesterol was increased in animals from the HFD+CCl4 group compared to the SD and HFD groups, without significant differences between the SD and HFD groups. Plasma triglycerides showed no significant difference between the groups. The HFD+CCl4 animals had increased collagen deposition in the liver compared with both SD and HFD groups. Hydroxyproline was also increased in the HFD+CCl4 group. Liver enzymes, alanine aminotransferase and aspartate aminotransferase, were increased in the HFD+CCl4 group, compared with SD and HFD groups. Also, CCl4 was able to trigger an inflammatory process in the liver of HFD-fed animals by promoting an increase of ~2 times in macrophage activity, ~6 times in F4/80 gene expression, and pro-inflammatory cytokines (IL-1b and TNFa), in addition to an increase in inflammatory pathway protein phosphorylation (IKKbp). HFD e HFD+CCl4 animals increased glucose intolerance compared with SD mice, associated with reduced insulin-stimulated AKT activity in the liver. Therefore, our study has shown that short-term HFD feeding associated with fructose and CCl4 can trigger non-alcoholic steatohepatitis and cause damage to glucose metabolism.

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ECOTOX ENVIRON SAFE

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J AGR FOOD CHEM

Zebrafish as a Model for Cardiovascular and Metabolic Disease: The Future of Precision Medicine

Article

Full-text available

Mar 2024

The zebrafish (Danio rerio) has emerged as an appreciated and versatile model organism for studying cardiovascular and metabolic diseases, offering unique advantages for both basic research and drug discovery. The genetic conservation between zebrafish and humans and their high fecundity and transparent embryos allow for efficient large-scale genetic and drug-oriented screening studies. Zebrafish possess a simplified cardiovascular system that shares similarities with mammals, making them particularly suitable for modeling various aspects of heart development, function, and disease. The transparency of zebrafish embryos enables the real-time visualization of cardiovascular dynamics, offering insights into early embryonic events and facilitating the study of heart-related anomalies. In metabolic research, zebrafish provide a cost-effective platform for modeling obesity, type 2 diabetes, hyperlipidemia, and other metabolic disorders. Their high reproductive rate allows for the generation of large cohorts for robust statistical analyses, while advanced genetic tools, such as CRISPR/Cas9, enable precise gene editing with which to model specific genetic mutations associated with human diseases. Zebrafish metabolic models have been instrumental in elucidating the molecular mechanisms underlying metabolic diseases, studying the effects of environmental factors, and identifying potential therapeutic targets. Additionally, the permeability of zebrafish embryos to small molecules facilitates drug discovery and screening, offering a rapid and economical approach to identifying compounds with therapeutic potential. In conclusion, zebrafish cardiovascular and metabolic disease models continue to contribute significantly to our perception of disease pathogenesis, providing a platform for translational research and developing novel therapeutic interventions. The versatility, scalability, and genetic manipulability of zebrafish position them as an invaluable asset in unraveling the complexities of cardiovascular and metabolic diseases. This review presents an overview of the zebrafish model’s key features and contributions to investigating cardiovascular and metabolic disorders. We discuss the benefits and drawbacks of using zebrafish models to study human disease and the critical findings revealed by the progress in this endeavor to date.

The function and application of edible fungal polysaccharides

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ADV APPL MICROBIOL

Living-donor liver transplantation for methylmalonic acidemia patient with hepatocellular carcinoma: A case report and literature review

Article

Mar 2024
PEDIATR TRANSPLANT

Background Methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in propionyl‐CoA (P‐CoA) catabolism; of note, liver neoplasms rarely occur as a long‐term complication of the disorder. Herein, we report the case of a patient with MMA and hepatocellular carcinoma (HCC) who was successfully treated with a living‐donor liver transplant (LDLT) following prior kidney transplantation. Case Report A 25‐year‐old male patient with MMA underwent LDLT with a left lobe graft because of metabolic instability and liver neoplasms. He had presented with chronic symptoms of MMA, which had been diagnosed by genetic testing. Additionally, he had undergone living‐donor kidney transplantation with his father as the donor due to end‐stage kidney disease 6 years before the LDLT. He had an episode of metabolic decompensation triggered by coronavirus disease in 2019. Imaging studies revealed an intrahepatic neoplasm in the right hepatic lobe. Due to concerns about metabolic decompensation after hepatectomy, LDLT was performed using a left lobe graft obtained from the patient's mother. Pathological findings were consistent with the characteristics of well‐to‐moderately differentiated HCC. The postoperative course was uneventful, and the patient was discharged 48 days after the LDLT without any complications. At the 9‐month follow‐up, the patient's condition was satisfactory, with sufficient liver graft function and without metabolic decompensation. Conclusion This case indicates that although HCC is a rare complication in patients with MMA, clinicians should be aware of hepatic malignancies during long‐term follow‐up.

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Soft Drink Consumption Linked with Fatty Liver in the Absence of Traditional Risk Factors

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Full-text available

Jan 2008
CAN J GASTROENTEROL

Little is known about dietary habits and their relationships with liver disease in nonalcoholic fatty liver disease (NAFLD) patients, particularly in the absence of obesity, diabetes or hyperlipidemia. OBJECTIVE: To assess the association between soft drink consumption and the presence of fatty liver in NAFLD patients who do not have classic risk factors. METHODS: Three hundred ten patients with NAFLD diagnosed by ultrasound were assessed for 36 months in a cross-sectional manner. Thirty-one patients (10%) who had NAFLD without classic risk factors were compared with 30 healthy controls. Physical activity was assessed during the preceding week and year, and every six months for 36 months. Data on daily dietary intake of food and soft drink, and the source of added sugar were collected during two seven-day periods, at the beginning of the study, and within two weeks after the metabolic tests by using a validated food questionnaire given by a trained dietician. Insulin resistance and lipid peroxidation were assessed by homeostasis model assessment-insulin resistance index (HOMA-IRI) and malondialdehyde (MDA) levels, respectively. RESULTS: Eighty per cent of patients (25 of 31) consumed an excessive amount of soft drink beverages (more than 50 g/day of added sugar) for 36 months, compared with 20% in healthy controls (P

Trends in Intake of Energy and Macronutrients—United States, 1971-2000

Article

Mar 2004

During 1971-2000, the prevalence of obesity in the United States increased from 14.5% to 30.9%.¹ Unhealthy diets and sedentary behaviors have been identified as the primary causes of deaths attributable to obesity.² Evaluating trends in dietary intake is an important step in understanding the factors that contribute to the increase in obesity. To assess trends in intake of energy (i.e., kilocalories [kcals]), protein, carbohydrate, total fat, and saturated fat during 1971-2000, CDC analyzed data from four National Health and Nutrition Examination Surveys (NHANES): NHANES I (conducted during 1971-1974), NHANES II (1976-1980), NHANES III (1988-1994), and NHANES 1999-2000. This report summarizes the results of that analysis, which indicate that, during 1971-2000, mean energy intake in kcals increased, mean percentage of kcals from carbohydrate increased, and mean percentage of kcals from total fat and saturated fat decreased (Figures 1 and 2). An expert advisory committee appointed by the U.S. Department of Health and Human Services and the U.S. Department of Agriculture (USDA) is conducting a review of the Dietary Guidelines for Americans.³ Revised guidelines will be published in 2005.

The Effects of Low-Carbohydrate versus Conventional Weight Loss Diets in Severely Obese Adults: One-Year Follow-up of a Randomized Trial

Article

May 2004

Linda Stern

Background: A previous paper reported the 6-month comparison of weight loss and metabolic changes in obese adults randomly assigned to either a low-carbohydrate diet or a conventional weight loss diet. Objective: To review the 1-year outcomes between these diets. Design: Randomized trial. Setting: Philadelphia Veterans Affairs Medical Center. Participants: 132 obese adults with a body mass index of 35 kg/m 2 or greater; 83% had diabetes or the metabolic syndrome. Intervention: Participants received counseling to either restrict carbohydrate intake to <30 g per day (low-carbohydrate diet) or to restrict caloric intake by 500 calories per day with <30% of calories from fat (conventional diet). Measurements: Changes in weight, lipid levels, glycemic control, and insulin sensitivity. Results: By 1 year, mean (±SD) weight change for persons on the low-carbohydrate diet was -5.1 ± 8.7 kg compared with -3.1 ± 8.4 kg for persons on the conventional diet. Differences between groups were not significant (-1.9 kg [95% Cl, -4.9 to 1.0 kg]; P = 0.20). For persons on the low-carbohydrate diet, triglyceride levels decreased more (P = 0.044) and high-density lipoprotein cholesterol levels decreased less (P = 0.025). As seen in the small group of persons with diabetes (n = 54) and after adjustment for covariates, hemoglobin A 1c levels improved more for persons on the low-carbohydrate diet These more favorable metabolic responses to a low-carbohydrate diet remained significant after adjustment for weight loss differences. Changes in other lipids or insulin sensitivity did not differ between groups. Limitations: These findings are limited by a high dropout rate (34%) and by suboptimal dietary adherence of the enrolled persons. Conclusion: Participants on a low-carbohydrate diet had more favorable overall outcomes at 1 year than did those on a conventional diet. Weight loss was similar between groups, but effects on atherogenic dyslipidemia and glycemic control were still more favorable with a low-carbohydrate diet after adjustment for differences in weight loss.

Fat Accumulation in the Liver Is Associated with Defects in Insulin Suppression of Glucose Production and Serum Free Fatty Acids Independent of Obesity in Normal Men

Article

Jul 2002

A. Seppala-Lindroos

Weight loss with a low-carbohydrate, mediterranean, or low-fat diet

Article

Jan 2008

Alcohol and Atherosclerosis

Article

Jun 1991

Daniel Steinberg

The Fructose Epidemic

Article

Robert Lustig

F ructose consumption (as both high fructose corn syr-up and sucrose) has increased coincidentally with the worldwide epidemics of obesity and metabolic syndrome. Fructose is a primary contributor to human disease as it is metabolized in the liver differently to glucose, and is more akin to that of ethanol. When consumed in large amounts, fructose promotes the same dose-dependent toxic effects as ethanol, promoting hypertension, hepatic and skeletal muscle insulin resistance, dyslipidemia and fatty liver disease. Also similar to ethanol, through di-rect stimulation of the central nervous system "hedonic pathway" and indirect stimulation of the "starvation path-way," fructose induces alterations in central nervous sys-tem energy signaling that lead to a vicious cycle of exces-sive consumption, with resultant morbidity and mortality. Fructose from any source should be regarded as "alcohol without the buzz." Obesity preven-tion and treatment is ineffective in the face of the current "fructose glut" in our food supply. We must learn from our experiences with ethanol and nicotine that regulation of the food industry, along with in-dividual and societal education, will be necessary to combat this fructose epidemic.

Hydroxyl Radical Mediates N ϵ-(Carboxymethyl)lysine Formation from Amadori Product

Article

May 1997

Recent studies demonstrated Nϵ-(carboxymethyl) lysine (CML) in several tissue proteins. Incubation of proteins with glucose leads through a Schiff base to Amadori products. Oxidative cleavage of Amadori products is considered as a major route to CML formationin vivo,whereas it is not known which reactive oxygen species (ROS) is involved. The present study is undertaken to identify such a ROS. We prepared heavily glycated human serum albumin (HSA) which contained a high level of Amadori products, but an undetectable level of CML. Incubation of glycated HSA with FeCl2, but not with H2O2, led to CML formation which was enhanced by H2O2, but inhibited by catalase or mannitol, whereas superoxide dismutase had no effect. Similar data were obtained by experiments using Boc-fructose-lysine as a model Amadori compound. These data indicate that hydroxyl radical generated by the reaction of Fe2+with H2O2mediates CML formation from Amadori compounds.

Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetylCoA carboxylases 1 and 2

Article

Mar 2006

D. B. Savage

A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats

Article

Sep 2006

Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). We used a high-fat, high-calorie solid diet (HFD) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HFD rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-α mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-α expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-α-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPARα ligand, to HFD-treated animals restored hepatic adiponectin and PPARα expression, reduced TNF-α hepatic levels, and ameliorated fatty liver and the degree of liver injury. Thus, our model mimics the most common features of NASH in humans and provides an ideal tool to study the role of individual pathogenetic events (as for PPARα down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury.

The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome

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