Emerging molecular targets for the treatment of nonalcoholic fatty liver disease.
ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, viral infection, or other specific causes of liver disease. Currently the most common chronic liver disease, affecting 30% of the Western world, NAFLD may progress to cirrhosis and end-stage liver disease and may increase the risk of developing diabetes and cardiovascular disease. Although its pathogenesis is unclear, NAFLD is tightly associated with insulin resistance and the metabolic syndrome. No established treatment exists, and current research is targeting new molecular mechanisms that underlie NAFLD and associated cardiometabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD: microRNAs, incretin analogs/antagonists, liver-specific thyromimetics, AMP-activated protein kinase activators, and nuclear receptors farnesoid X receptor and pregane X receptor.
[Show abstract] [Hide abstract]
ABSTRACT: In the present study, we investigated the effects of viscothionin, a compound isolated from Korean mistletoe (Viscum album coloratum) on nonalcoholic fatty liver disease (NAFLD) in both in vitro and in vivo models. We discovered a connection between viscothionin and the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, which is involved in lipid metabolism. Viscothionin was shown to significantly attenuate lipid accumulation in HepG2 cells treated with oleic acid, which induces lipid accumulation. Moreover, the phosphorylation of AMPK and acetyl-coenzyme A carboxylase in HepG2 cells were increased by viscothionin treatment. Viscothionin was orally administered to high fat diet-induced obese mice and subsequently evaluated histopathological analysis associated with AMPK signaling pathways. A significant reduction in the extent of hepatic steatosis was revealed in viscothionin-treated obese mice. Thus, viscothionin mediates its beneficial effects on NAFLD via AMPK signaling pathways, suggesting a potential target for novel treatments against NAFLD.Journal of Agricultural and Food Chemistry 11/2014; 62(49). DOI:10.1021/jf503535s · 3.11 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Ethnopharmacological relevance: Magnolia officinalis (MO) is a traditional Chinese herbal medicine that has been used in clinical practice to treat liver disease. The aim of this study is to examine the effects of MO on the development of nonalcoholic fatty liver in hepatocytes. Materials and methods: Human hepatoma-derived HepG2 cells and mouse normal FL83B hepatocytes were exposed to 0.5 mM free fatty acids (FFAs; oleate:palmitate, 2:1) for 24 h to simulate conditions of nonalcoholic fatty liver in vitro. The cells were treated with a standardized MO extract 1 h prior to FFA exposure. Results: MO pretreatment attenuated the increases in intracellular lipid accumulation and triglyceride content in FFA-exposed hepatocytes in a dose-dependent manner. MO pretreatment significantly inhibited both sterol regulatory element-binding protein (SREBP)-1c activation and increases in fatty acid translocase, fatty acid synthase, and stearoyl CoA desaturase-1 protein expression in FFA-exposed hepatocytes in a dose-dependent manner. MO pretreatment markedly induced adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in hepatocytes. Compound C, an AMPK inhibitor, blocked the inhibitory effect of MO on the increases in intracellular lipid accumulation and triglyceride content induced by FFAs. In hepatocytes pretreated with compound C, MO failed to inhibit SREBP-1c activation and the increases in fatty acid translocase, fatty acid synthase, and stearoyl-CoA desaturase-1 protein expression induced by FFAs. Conclusions: Our results indicate that MO attenuates triglyceride biosynthesis and accumulation induced by FFAs in hepatocytes, suggesting its pharmacological potential for the prevention of nonalcoholic fatty liver disease. These effects may be mediated by the inhibition of SREBP-1c via AMPK phosphorylation.Journal of Ethnopharmacology 09/2014; 157. DOI:10.1016/j.jep.2014.09.031 · 2.94 Impact Factor
Journal of Gastroenterology and Hepatology 08/2013; 28(S1). DOI:10.1111/jgh.12033 · 3.63 Impact Factor