Toll-Like Receptor 4 Is Involved in the Development of Fructose-Induced Hepatic Steatosis in Mice

A link between dietary fructose intake, gut-derived endotoxemia, and nonalcoholic fatty liver disease (NARD) has been suggested by the results of human and animal studies. To further investigate the role of gut-derived endotoxin in the onset of fructose-induced NARD, Toll-like receptor (TLR-) 4-mutant (C3H/HeJ) mice and wildtype (C3H/HouJ) mice were either fed plain water or water enriched with 30% fructose for 8 weeks. Hepatic steatosis, plasma alanine aminotransferase (ALT), and markers of insulin resistance as weft as portal endotoxin levels were determined. Hepatic levels of myeloid. differentiation factor 88 (MyD88), interferon regulatory factor (ERF) 3 and 7, and tumor necrosis factor alpha (TNF alpha) as well as markers of lipid peroxidation were assessed. Chronic intake of 30% fructose solution caused a significant increase in hepatic steatosis and plasma ALT levels in wildtype animals in comparison to water controls. In fructose-fed TLR-4 mutant mice, hepatic triglyceride accumulation was significantly reduced by approximate to 40% in comparison to fructose-fed wildtype mice and plasma ALT levels were at the level of water-fed controls. No difference in portal endotoxin concentration between fructose-fed wildtype and TLR-4-mutant animals was detected. In contrast, hepatic lipid peroxidation, MyD88, and TNF alpha levels were significantly decreased in fructose-fed TLR-4-mutant mice in comparison to fructose-fed wildtype mice, whereas IRF3 and IRF7 expression remained unchanged. Markers of insulin resistance (eg., plasma TNFa retinol binding protein 4, and hepatic phospho-AKT) were only altered in fructose-fed wildtype animals. Conclusion: Taken together, these data further support the hypothesis that in mice the onset of fructose-induced NARD is associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells. (HEPATOLOGY 200950: 1094-1104.)