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5-cholesten-3beta,25-diol 3-sulfate decreases lipid accumulation in diet-induced nonalcoholic fatty liver disease mouse model Xu L; Kim JK; Bai Q; Zhang X; Kakiyama G; Min HK; Sanyal AJ; Pandak WM; Ren SMol Pharmacol 2013[Mar]; 83 (3): 648-58Sterol regulatory element-binding protein-1c (SREBP-1c) increases lipogenesis at the transcriptional level, and its expression is upregulated by liver X receptor alpha (LXRalpha). The LXRalpha/SREBP-1c signaling may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We previously reported that a cholesterol metabolite, 5-cholesten-3beta,25-diol 3-sulfate (25HC3S), inhibits the LXRalpha signaling and reduces lipogenesis by decreasing SREBP-1c expression in primary hepatocytes. The present study aims to investigate the effects of 25HC3S on lipid homeostasis in diet-induced NAFLD mouse models. NAFLD was induced by feeding a high-fat diet (HFD) in C57BL/6J mice. The effects of 25HC3S on lipid homeostasis, inflammatory responses, and insulin sensitivity were evaluated after acute treatments or long-term treatments. Acute treatments with 25HC3S decreased serum lipid levels, and long-term treatments decreased hepatic lipid accumulation in the NAFLD mice. Gene expression analysis showed that 25HC3S significantly suppressed the SREBP-1c signaling pathway that was associated with the suppression of the key enzymes involved in lipogenesis: fatty acid synthase, acetyl-CoA carboxylase 1, and glycerol-3-phosphate acyltransferase. In addition, 25HC3S significantly reduced HFD-induced hepatic inflammation as evidenced by decreasing tumor necrosis factor and interleukin 1 alpha/beta mRNA levels. A glucose tolerance test and insulin tolerance test showed that 25HC3S administration improved HFD-induced insulin resistance. The present results indicate that 25HC3S as a potent endogenous regulator decreases lipogenesis, and oxysterol sulfation can be a key protective regulatory pathway against lipid accumulation and lipid-induced inflammation in vivo.|Acetyl-CoA Carboxylase/genetics/metabolism[MESH]|Acetyltransferases/genetics/metabolism[MESH]|Animals[MESH]|Cholesterol Esters/*pharmacology[MESH]|Diet, High-Fat/*adverse effects[MESH]|Fatty Acids/metabolism[MESH]|Fatty Liver/blood/chemically induced/*drug therapy/genetics/metabolism[MESH]|Female[MESH]|Gene Expression/genetics[MESH]|Glucose Tolerance Test/methods[MESH]|Glycerol-3-Phosphate O-Acyltransferase/genetics/metabolism[MESH]|Hydroxycholesterols/*pharmacology[MESH]|Inflammation/metabolism[MESH]|Insulin Resistance/genetics[MESH]|Insulin/genetics/metabolism[MESH]|Interleukin-1alpha/genetics/metabolism[MESH]|Interleukin-1beta/genetics/metabolism[MESH]|Lipid Metabolism/*drug effects/genetics[MESH]|Lipids/*blood[MESH]|Liver/drug effects/*metabolism[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Non-alcoholic Fatty Liver Disease[MESH]|Signal Transduction/drug effects/genetics[MESH]|Sterol Regulatory Element Binding Protein 1/genetics/metabolism[MESH]|Tumor Necrosis Factor-alpha/genetics/metabolism[MESH]|fas Receptor/genetics/metabolism[MESH] |
