ABSTRACT
YHK has antioxidant properties, has a hypoglycemic effect, and may reduce plasma lipid levels. In this study, we examined the hepatic expression of PPAR-alpha and -gamma and MTP in ob/ob mice receiving or not receiving YHK. Ob/ob mice were assigned to receive oral YHK (20 mg/kg/day) fed solution (methionine/choline-deficient [MCD] diet+YHK group) or vehicle (MCD group) by gavage for 4 weeks. Liver fragments were collected for histologic examination and mRNA isolation. PPAR-alpha and -gamma and MTP gene expression was examined by RT-qPCR. YHK treatment was associated with NASH prevention, weight loss, and reduction of visceral fat and of serum concentrations of aminotransferases in comparison to the MCD group. YHK promoted an increment in PPAR-alpha and MTP and a decrement in PPAR-gamma mRNA contents. These findings suggest that modulation of PPAR-alpha and -gamma and MTP RNA expression may be implicated in the protective effect of YHK in experimental NASH, limiting hepatocyte lipid accumulation.
Subject(s)
Carrier Proteins/genetics , Fatty Liver/metabolism , Gene Expression/genetics , PPAR alpha/genetics , PPAR gamma/genetics , Plant Preparations/therapeutic use , RNA, Messenger/genetics , Animals , Carrier Proteins/biosynthesis , Carrier Proteins/drug effects , Disease Models, Animal , Disease Progression , Fatty Liver/drug therapy , Fatty Liver/genetics , Gene Expression/drug effects , Hepatocytes/metabolism , Hepatocytes/pathology , Male , Mice , Mice, Obese , Microsomes, Liver , PPAR alpha/biosynthesis , PPAR alpha/drug effects , PPAR gamma/biosynthesis , PPAR gamma/drug effects , Phytotherapy/methods , Reverse Transcriptase Polymerase Chain Reaction , Treatment OutcomeABSTRACT
BACKGROUND: Oxidative stress plays a role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Yo jyo hen shi ko (YHK) is a complex compound purported to reduce reactive oxygen species (ROS) by blocking the propagation of radical-induced reactions. The aim of this study was to evaluate the role of the effect of YHK in experimental NASH. METHODS: NASH was induced in male ob/ob mice by a high-fat (HF) diet or methionine/choline-deficient (MCD) diet for 4 weeks. YHK-treated animals received YHK solution orally (20 mg/kg/day) in both experimental diets (n=6; each group) while control animals received only vehicle. RESULTS: The MCD and HF groups developed moderate diffuse macrosteatosis, hepatocellular ballooning, and a diffuse inflammatory infiltrate. With the addition of YHK, there was a marked reduction in macrosteatosis in both groups. This was associated with decreased lipoperoxide and reduced glutathione-GSH concentrations as well as reduced serum aminotransferases and improved histological markers of inflammation. These changes were also associated with weight loss in the MCD+YHK group and diminished weight gain in the HF+YHK group. CONCLUSION: YHK therapy blunts the development of macrosteatosis in these models of NASH and significantly reduces markers of oxidative stress. YHK also diminishes weight gain in this obesity prone model. Our findings warrant further study on the mechanisms involved with these effects.
Subject(s)
Choline Deficiency , Dietary Fats/administration & dosage , Drugs, Chinese Herbal/pharmacology , Fatty Liver/prevention & control , Hepatitis/prevention & control , Methionine/deficiency , Animals , Biomarkers/metabolism , Body Weight , Choline Deficiency/etiology , Diet , Dose-Response Relationship, Drug , Lipids/blood , Liver/drug effects , Liver/pathology , Male , Mice , Mice, Obese , Oxidative Stress , Transaminases/bloodABSTRACT
BACKGROUND/AIMS: To understand the molecular mechanisms underlying non-alcoholic steatohepatitis (NASH) prevention by S-nitroso-N-acetylcysteine (SNAC), an NO donor that inhibits lipid peroxidation, we examined hepatic differentially expressed genes between ob/ob mice receiving or not SNAC treatment concomitantly with a methionine-choline deficient (MCD) diet. METHODS: Ob/ob mice were assigned to receive oral SNAC fed solution (MCD+SNAC group) or vehicle (MCD group) by gavage. After four weeks, histopathological analysis and microarray hybridizations were conducted in liver tissues from groups. GeneSifter system was used to identify differentially expressed genes and pathways according to Gene Ontology. RESULTS: NASH was absent in the MCD+SNAC group and no significant changes in food intake or body weight were observed in comparison to MCD group. After SNAC treatment, several genes belonging to oxidative phosphorylation, fatty acid biosynthesis, fatty acid metabolism and glutathione metabolism pathways were down-regulated in comparison to the MCD group. CONCLUSIONS: SNAC treatment promotes down regulation of several genes from fatty acid (FA) metabolism related pathways, possibly through abrogation of the cytotoxic effects of reactive oxygen species and lipid peroxides with consequent prevention of mitochondrial overload. Further studies are required to investigate the clinical implications of these findings, in attempt to develop novel therapeutic strategies for NAFLD treatment.
