Abstract
Fructose intake is being discussed as a key dietary factor in the development of nonalcoholic fatty liver disease (NAFLD). Bile acids have been shown to modulate energy metabolism. We tested the effects of bile acids on fructose-induced hepatic steatosis. In C57BL/6J mice treated with a combination of chenodeoxycholic acid and cholic acid (100 mg/kg body weight each) while drinking water or a 30% fructose solution for eight weeks and appropriate controls, markers of hepatic steatosis, portal endotoxin levels, and markers of hepatic lipogenesis were determined. In mice concomitantly treated with bile acids, the onset of fructose-induced hepatic steatosis was markedly attenuated compared to mice only fed fructose. The protective effects of the bile acid treatment were associated with a downregulation of tumor necrosis factor (TNF)α, sterol regulatory element-binding protein (SREBP)1, FAS mRNA expression, and lipid peroxidation in the liver, whereas hepatic farnesoid X receptor (FXR) or short heterodimer partner (SHP) protein concentration did not differ between groups fed fructose. Rather, bile acid treatment normalized occludin protein concentration in the duodenum, portal endotoxin levels, and markers of Kupffer cell activation to the level of water controls. Taken together, these data suggest that bile acids prevent fructose-induced hepatic steatosis in mice through mechanisms involving protection against the fructose-induced translocation of intestinal bacterial endotoxin.
Highlights
Fructose intake is being discussed as a key dietary factor in the development of nonalcoholic fatty liver disease (NAFLD)
In livers of fructose-fed mice concomitantly treated with bile acids, hepatic lipid and triglyceride levels were only increased by ف2.2-fold and ف1.3-fold, respectively, compared to controls treated with bile acids
In accordance with these findings, ALT levels were significantly higher in plasma of fructose-fed mice; plasma ALT levels did not differ between controls and fructosefed mice treated with bile acids (Table 2)
Summary
Fructose intake is being discussed as a key dietary factor in the development of nonalcoholic fatty liver disease (NAFLD). The hypothesis that a diet rich in mono- and disaccharides, such as fructose and sucrose, might play a critical role in the pathogenesis of NAFLD is supported by a number of studies performed in animals In these studies, it was shown that an increased consumption of fructose (e.g., up to 60% of daily calories derived from fructose) resulted in an increased lipid accumulation in the liver, which was accompanied by insulin resistance, elevated plasma triglyceride levels, and oxidative stress [5,6,7,8,9]. Our group was able to show that hepatic steatosis resulting from chronic intake of fructose is associated with a loss of the tight junction protein occludin in the duodenum, an increased translocation of bacterial endotoxins from the intestine, and an induction of tumor necrosis factor (TNF)␣ in the liver of mice [7, 10, 11].
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