Sulfated oxysterol, 25HC3S, is a potent regulator of lipid metabolism in human hepatocytes.
Recently, a novel oxysterol, 5-cholesten-3beta, 25-diol 3-sulfate (25HC3S) was identified in primary rat hepatocytes following overexpression of the cholesterol transport protein, StarD1. This oxysterol was also detected in human liver nuclei. In the present study, 25HC3S was chemically synthesized. Addition of 25HC3S (6 microM) to human hepatocytes markedly inhibited cholesterol biosynthesis. Quantitative RT-PCR and Western blot analysis showed that 25HC3S markedly decreased HMG-CoA reductase mRNA and protein levels. Coincidently, 25HC3S inhibited the activation of sterol regulatory element binding proteins (SREBPs), suggesting that inhibition of cholesterol biosynthesis occurred via blocking SREBP-1 activation, and subsequently by inhibiting the expression of HMG CoA reductase. 25HC3S also decreased SREBP-1 mRNA levels and inhibited the expression of target genes encoding acetyl CoA carboxylase-1 (ACC-1) and fatty acid synthase (FAS). In contrast, 25-hydroxycholesterol increased SREBP1 and FAS mRNA levels in primary human hepatocytes. The results imply that 25HC3S is a potent regulator of SREBP mediated lipid metabolism.
Ren
Shunlin
S
Department of Medicine, Veterans Affairs McGuire Medical Center/Virginia Commonwealth University, Richmond, VA 23249, USA. sren@vcu.edu
Li
Xiaobo
X
Rodriguez-Agudo
Daniel
D
Gil
Gregorio
G
Hylemon
Phillip
P
Pandak
William M
WM
D001483:Base Sequence; D015153:Blotting, Western; D002784:Cholesterol / Q000096:biosynthesis; D002788:Cholesterol Esters / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D017931:DNA Primers; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013261:Sterols / Q000737:chemistry / Q000494:pharmacology*; D013431:Sulfates / Q000737:chemistry
C534977:25-hydroxycholesterol 3-sulfate; D002788:Cholesterol Esters; D017931:DNA Primers; D006888:Hydroxycholesterols; D012333:RNA, Messenger; D013261:Sterols; D013431:Sulfates; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases