title: 5-cholesten-3β,25-diol 3-sulfate decreases lipid accumulation in diet-induced nonalcoholic fatty liver disease mouse model.
abstract: Sterol regulatory element-binding protein-1c (SREBP-1c) increases lipogenesis at the transcriptional level, and its expression is upregulated by liver X receptor α (LXRα). The LXRα/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-3β,25-diol 3-sulfate (25HC3S), inhibits the LXRα 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 α/β 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.
authors.affiliation: McGuire Veterans Affairs Medical Center/Virginia Commonwealth University, Research 151, Richmond, VA 23249, USA.
authors.forename: Leyuan
authors.initials: L
authors.lastname: Xu
authors.forename: Jin Koung
authors.initials: JK
authors.lastname: Kim
authors.forename: Qianming
authors.initials: Q
authors.lastname: Bai
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Genta
authors.initials: G
authors.lastname: Kakiyama
authors.forename: Hae-Ki
authors.initials: HK
authors.lastname: Min
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.forename: Shunlin
authors.initials: S
authors.lastname: Ren
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002788:Cholesterol Esters / Q000494:pharmacology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005951:Glucose Tolerance Test / Q000379:methods; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C534977:25-hydroxycholesterol 3-sulfate; D002788:Cholesterol Esters; D005227:Fatty Acids; D006888:Hydroxycholesterols; D007328:Insulin; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008055:Lipids; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; D005992:Glycerol-3-Phosphate O-Acyltransferase; C571223:glycerol-3-phosphate acyltransferase 2, mouse; D000103:Acetyl-CoA Carboxylase