Elsevier

Journal of Hepatology

Volume 48, Issue 6, June 2008, Pages 993-999
Journal of Hepatology

Fructose consumption as a risk factor for non-alcoholic fatty liver disease

https://doi.org/10.1016/j.jhep.2008.02.011Get rights and content

Background/Aims

While the rise in non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity and diabetes, a significant increase in dietary fructose consumption in industrialized countries has also occurred. The increased consumption of high fructose corn syrup, primarily in the form of soft drinks, is linked with complications of the insulin resistance syndrome. Furthermore, the hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion. We hypothesize that increased fructose consumption contributes to the development of NAFLD.

Methods

A dietary history and paired serum and liver tissue were obtained from patients with evidence of biopsy-proven NAFLD (n = 49) without cirrhosis and controls (n = 24) matched for gender, age (±5 years), and body mass index (±3 points).

Results

Consumption of fructose in patients with NAFLD was nearly 2- to 3-fold higher than controls [365 kcal vs 170 kcal (p < 0.05)]. In patients with NAFLD (n = 6), hepatic mRNA expression of fructokinase (KHK), an important enzyme for fructose metabolism, and fatty acid synthase, an important enzyme for lipogenesis were increased (p = 0.04 and p = 0.02, respectively). In an AML hepatocyte cell line, fructose resulted in dose-dependent increase in KHK protein and activity.

Conclusions

The pathogenic mechanism underlying the development of NAFLD may be associated with excessive dietary fructose consumption.

Introduction

Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, is the most common explanation for liver aminotransferase elevation in obesity [1]. The prevalence of NAFLD exceeds the combined prevalence of chronic viral and alcohol-associated liver disease in the general United States population [2]. Population-based studies, such as NHANES III and the Dallas Heart Study [3], [4] confirm that obesity and type 2 diabetes are highly correlated with NAFLD. As the prevalence of obesity and diabetes increase, NAFLD has become the leading cause of chronic liver disease in developed countries.

The dramatic rise in prevalence of NAFLD and the metabolic syndrome strongly suggest a role for environmental factors in disease pathogenesis. Most attention has focused on increased energy (caloric) intake coupled with reduced physical activity as central mechanisms contributing to the obesity epidemic. However, an important, but not well-appreciated change in dietary habit has been the substantial increase in dietary fructose consumption acquired from sucrose and high fructose corn syrup (HFCS), a common sweetener used in the food industry [5]. For example, soft drinks and fruit drinks, which are a major source of HFCS or sugar, have increased from 3.9% of total energy intake in 1977 to 9.2% of total energy intake in 2001 [6]. Soft drink consumption has recently been linked with increased risk for weight gain [7], [8], type-2 diabetes [8], [9] and other features of the metabolic syndrome [10]. Soft drink consumption is associated with cardiometabolic risk factors and the metabolic syndrome in middle-aged adults [10], [11] and with the development of obesity in children [12].

Many studies suggest that the mechanism by which sugar or HFCS may induce metabolic syndrome is due to the fructose content [13], [14], [15], [16]. In animal models, diets high in fructose induce features of the metabolic syndrome including weight gain, insulin resistance, hypertriglyceridemia, and hypertension [17]. Similar effects are not observed with the administration of other simple sugars such as glucose [18]. Fructose (or sucrose) administration to humans also causes features of metabolic syndrome [13], [15], [16].

While it has not been emphasized, fructose may have a role in the pathogenesis of NAFLD. Fructose is lipogenic and stimulates triglyceride synthesis [19]. Splanchnic perfusion studies demonstrate that fructose produces higher rates of triglyceride secretion from the liver than equimolar amounts of glucose [20]. The long-term administration of fructose to rats results in hepatic macro- and microvesicular steatosis with a 198% increase in hepatic triglycerides and an 89% increase in hepatic cholesterol concentration [21]. Ducks fed high fructose diets also develop fatty liver [22]. Furthermore, the administration of a diet with 25% of total energy as sucrose (which contains 50% fructose) resulted in a rise in hepatic ALT and AST levels within 18 days [23]. This study, which was performed nearly 25 years ago, is all the more alarming as current sugar intake of Americans is in this same range [24]. Indeed, total fructose intake averages approximately 12% of total energy intake and may increase to 15% in some subgroups in the US population [15].

A potential mechanism by which fructose may cause liver injury also exists. The metabolism of fructose is distinct from glucose. Before converging with the glycolytic pathway, initial fructose metabolism involves phosphorylation of fructose to fructose-1-phosphate by fructokinase (ketohexokinase, KHK) using the substrate ATP. Unlike glucokinase, the phosphorylation of fructose by fructokinase is specific for fructose and not rate limited. The high activity of fructokinase in phosphorylating fructose to fructose-1-phosphate in the liver, could result in hepatic ATP depletion [15]. Indeed, fructose has been shown to cause ATP depletion in humans [25], [26], [27], and recovery from fructose-induced ATP depletion was found to be delayed in subjects with NALFD in studies that used phosphorus-1 magnetic resonance spectrosocopy to assess hepatic metabolism [27], [28]. In some regards, fructose-induced ATP depletion resembles hepatic ischemia [29]. In rats, fructose administration increases hepatic lipid peroxidation and activation of inflammatory pathways [30], [31]. We have also found that incubation of endothelial cells or renal tubular cells with postprandial concentrations of fructose reduces intracellular ATP and activates proinflammatory and pro-oxidative responses [Cirillo P, Sautin YY and Johnson RJ, unpublished]. Therefore, high fructose consumption may contribute to NAFLD pathogenesis because fructose-induced ATP depletion promotes hepatic necroinflammation.

Despite the evidence suggesting that fructose may be involved in the pathogenesis of NAFLD, no studies have specifically investigated this relationship. We conducted a case–control study to assess whether there is increased fructose intake in those with NAFLD and whether fructose correlates with features of the metabolic syndrome of insulin resistance. In addition, since fructose upregulates KHK activity in the liver and intestines of rats fed a high fructose diet [32], [33], we examined whether KHK is increased in the liver of subjects with and without NAFLD.

Section snippets

Patients and methods

Following the approval by the Institutional Review Board of the University of Florida, we prospectively collected demographic, medical, and dietary information on patients with biopsy-proven NAFLD (n = 49) and no evidence of NAFLD (n = 24) on liver biopsy. Each patient diagnosed with NAFLD underwent a comprehensive medical evaluation to exclude alternative causes for chronic liver disease. The presence of NAFLD was established by a comprehensive medical history, the presence of abnormal liver

Consumption of non-dietary soft drinks and other sweetened beverages

Despite using the most conservative estimate of HFCS consumption possible, patients with biopsy-proven NAFLD (n = 49) had increased daily consumption of HFCS or sugar containing beverages when compared to their matched controls (n = 24) [365 kcal/day vs 170 kcal/day, fructose intake, p < 0.05]. Fig. 1 depicts the difference in fructose energy consumption between the groups. For comparison, the mean total energy intake from sweetened beverages in adults from the NHANES study performed in 1999–2001 was

Discussion

The new millennium has witnessed a modern epidemic of obesity, metabolic syndrome, and diabetes. An increasingly recognized complication is non-alcoholic fatty liver disease (NAFLD), which can progress to cirrhosis over time in some individuals. In this study we investigated whether fructose could play a role in NAFLD, based on the studies showing that fructose intake induces both features of metabolic syndrome and NAFLD in animals [17], [22] and correlates with the epidemic of metabolic

Acknowledgements

Support for this study comes in part from NIH Grants DK-52121, HL-68607, and DK-79352 and generous funds from Gatorade. M.F. Abdelmalek is supported by a NIH career development award, K23 DK062116.

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    R.J. Johnson and Y. Sautin are listed as inventors on patent applications by the University of Florida related to the role of fructose in hypertension and metabolic syndrome. Dr. Johnson has also written a book on fructose for the lay public (Rodale Press, 2008). NIH funded study (Grants DK-52121, HL-68607, DK-79352 and K23 DK062116).

    Present address: Department of Genetics, University of Alabama at Birmingham, Kaul 748, 720 20th Street South, Birmingham, AL 35294, United States. Tel.: +1 205 934 6952; fax: +1 205 975 5689.

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