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

Abstract

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.

Figure 1. HFCS consumption

Energy consumption of fructose from sweetened beverages in patients with NAFLD was estimated as 356 kcal /day compared with 170 kcal /day in control patients with non -steatotic livers (p<0.05).

Figure 2. Tissue Realtime PCR from Human Liver Tissue

The mRNA expression of fructokinase (KHK), an important enzyme for fructose metabolism, and fatty acid synthase (FAS), an important enzyme for lipogenesis, are increased in NAFLD livers compared with non-steatotic liver control specimens (p<0.05). The mRNA expression of xanthine dehydrogenase (XDH) shows a trend for upregulation in NAFLD group but was not statistically significant (p=0.16).

Figure 3. Effect of fructose on the enzymatic activity and expression of ketohexokinase (fructokinase, KHK) in the mouse hepatocytes AML-12

(A) Effect of fructose on the KHK activity. N=3 performed in triplicates. *, ** p<0.05, 0.01, respectively, in comparison to fructose-free control. (B) Effect of fructose on KHK expression. Representative blots from three independent experiments are shown. Densitometry is expressed as the ratio of the optical density of KHK band to GAPDH band detected after stripping the membrane.