α-Tocopherol suppresses hepatic steatosis by increasing CPT-1 expression in a mouse model of diet-induced nonalcoholic fatty liver disease.

AIM: Antioxidant therapy for with vitamin E appears to be effective for the treatment of nonalcoholic fatty liver disease　(NAFLD). However, the mechanism of action and optimal therapeutic dosage is unclear. The present study was undertaken to examine whether the effects of α-tocopherol (α-Toc) on NAFLD are dose-dependent in a diet-induced obese model. METHODS: Male mice were fed standard chow, high-fat (HF) diet, HF diet with low-dose, or with high dose of α-Toc supplementation. Histological findings, triglyceride content, and the levels of protein expression related to fatty acid synthesis/oxidation such as carnitine palmitoyltransferase I (CPT-1) of liver were evaluated. In addition, 2-tetradecylglycidic acid (TDGA), a CPT-1 inhibitor, was administered to mice fed HF diet with low-dose of α-Toc. Finally, HepG2 cells in fat-loaded environment were treated with 0-50 µM α-Toc. RESULTS: Treatment of low-dose of α-Toc decreased HF-induced hepatic fat accumulation, but this finding was not observed in treatment of high dose of α-Toc. HF-induced reduction of CPT-1 was attenuated with low-dose of α-Toc but not with high dose of α-Toc. TDGA suppressed the improvement of histological findings in liver induced by low-dose of α-Toc treatment. CPT-1 expression in HepG2 cells increased in response to low-dose of α-Toc, but not in high dose. CONCLUSIONS: Dual action of α-Toc on CPT-1 protein levels was observed. The effect of vitamin E on NAFLD may be not be dose-dependent.

Supplementation of branched-chain amino acids decreases fat accumulation in the liver through intestinal microbiota-mediated production of acetic acid.

Non-alcoholic fatty liver disease (NAFLD) is a significant problem because its prevalence is increasing worldwide. Recent animal studies have identified gut microbiota as a potentially important player in the pathogenesis of NAFLD. Previously, we reported that the administration of branched-chain amino acids (BCAAs) reduces hepatic fat accumulation in experimental animal models. This study aimed to clarify how changes in the intestinal microbial flora following the administration of BCAAs affect a high-fat diet (HF)-induced fat accumulation in the liver. We examined whether the administration of BCAAs alters the development of hepatic fat accumulation as well as intestinal microbial flora. The oral administration of BCAAs (3% kcal) induced a significant increase in Ruminococcus flavefaciens (R. flavefaciens) and portal acetic acid levels, and it reduced hepatic fat accumulation in HF-fed rats. In addition, BCAAs reduced the expression of the lipogenesis-related genes FAS and ACC in the liver. Furthermore, we observed that R. flavefaciens is essential for promoting a BCAA-induced reduction in hepatic fat accumulation. These data suggest that BCAA treatment induces the proliferation of intestinal flora including R. flavefaciens and that portal acetic acid synthesized from intestinal flora improves NAFLD by downregulating the expression of FAS and ACC in the liver.

Involvement of stomach ghrelin and hypothalamic neuropeptides in tumor necrosis factor-alpha-induced hypophagia in mice.

This study aimed to clarify the interaction of tumor necrosis factor-alpha (TNF-alpha), an anorexigenic cytokine, with ghrelin, an orexigenic peptide secreted by the stomach lining, and hypothalamic neuropeptides in the regulation of food intake in mice. The peripheral administration of TNF-alpha dose-dependently decreased the 24-h cumulative food intake compared with the administration of saline. Reduced food intake was observed at 6 h and 24 h. The same TNF-alpha treatment significantly decreased the plasma level of ghrelin at 6 h and 24 h after treatment compared with the control levels. These changes were accompanied by a significant reduction in the expression of ghrelin mRNA in the stomach at 24 h after treatment. TNF-alpha treatment also resulted in a significant increase in expression of pro-opiomelanocortin (POMC) mRNA and a significant decrease in expression of agouti-related protein (AGRP) mRNA in the hypothalamus at 6 h after treatment. Finally, the pre-administration of ghrelin, reversed the TNF-alpha-induced hypophagia in mice at 6 and 24 h. Taken together, these findings suggest that hypothalamic POMC and AGRP and stomach ghrelin may be involved in TNF-alpha-induced hypophagia in mice.