Document Detail

5-cholesten-3β,25-diol 3-sulfate decreases lipid accumulation in diet-induced nonalcoholic fatty liver disease mouse model.
MedLine Citation:
PMID:  23258548     Owner:  NLM     Status:  MEDLINE    
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.
Leyuan Xu; Jin Koung Kim; Qianming Bai; Xin Zhang; Genta Kakiyama; Hae-Ki Min; Arun J Sanyal; William M Pandak; Shunlin Ren
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-12-20
Journal Detail:
Title:  Molecular pharmacology     Volume:  83     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-19     Completed Date:  2013-07-05     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  648-58     Citation Subset:  IM    
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MeSH Terms
Acetyl-CoA Carboxylase / genetics,  metabolism
Acetyltransferases / genetics,  metabolism
Antigens, CD95 / genetics,  metabolism
Cholesterol Esters / pharmacology*
Diet, High-Fat / adverse effects*
Fatty Acids / metabolism
Fatty Liver / blood,  chemically induced,  drug therapy*,  genetics,  metabolism
Gene Expression / genetics
Glucose Tolerance Test / methods
Glycerol-3-Phosphate O-Acyltransferase / genetics,  metabolism
Hydroxycholesterols / pharmacology*
Inflammation / metabolism
Insulin / genetics,  metabolism
Insulin Resistance / genetics
Interleukin-1alpha / genetics,  metabolism
Interleukin-1beta / genetics,  metabolism
Lipid Metabolism / drug effects*,  genetics
Lipids / blood*
Liver / drug effects,  metabolism*
Mice, Inbred C57BL
Signal Transduction / drug effects,  genetics
Sterol Regulatory Element Binding Protein 1 / genetics,  metabolism
Tumor Necrosis Factor-alpha / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/25-hydroxycholesterol 3-sulfate; 0/Antigens, CD95; 0/Cholesterol Esters; 0/Fatty Acids; 0/Hydroxycholesterols; 0/Insulin; 0/Interleukin-1alpha; 0/Interleukin-1beta; 0/Lipids; 0/Srebf1 protein, mouse; 0/Sterol Regulatory Element Binding Protein 1; 0/Tumor Necrosis Factor-alpha; EC 2.3.1.-/Acetyltransferases; EC 2.3.1.-/aminoglycoside N1-acetyltransferase; EC O-Acyltransferase; EC acyltransferase 2, mouse; EC Carboxylase

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