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标题：Chenodeoxycholic acid suppresses the activation of acetyl-coenzyme A carboxylase-{alpha} gene transcription by the liver X receptor agonist T0-901317
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作者：Talukdar, Saswata ; Bhatnagar, Sushant ; Dridi, Sami 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2007
卷号：48
期号：12
页码：2647-2663
DOI：10.1194/jlr.M700189-JLR200
出版社：American Society for Biochemistry and Molecular Biology
摘要：The therapeutic utility of liver X receptor (LXR) agonists intreating atherosclerosis is limited by an undesired accumulationof triglycerides in the blood and liver. This effect is causedby an increase in the transcription of genes involved in fattyacid synthesis. Here, we show that the primary bile acid, chenodeoxycholicacid (CDCA), antagonizes the stimulatory effect of the syntheticLXR agonist, T0-901317, on the expression of acetyl-coenzymeA carboxylase- ${alpha}$ (ACC ${alpha}$ ) and other lipogenic enzymes in chick embryohepatocyte cultures. CDCA inhibits T0-901317-induced ACC ${alpha}$ transcriptionby suppressing the enhancer activity of a LXR response unit(–101 to –71 bp) that binds LXR and sterol-regulatoryelement binding protein-1 (SREBP-1). We also demonstrate thatCDCA decreases the expression of SREBP-1 in the nucleus andthe acetylation of histone H3 and H4 at the ACC ${alpha}$ LXR responseunit. The CDCA-mediated reduction in ACC ${alpha}$ expression is associatedwith a decrease in the expression of peroxisome proliferator-activatedreceptor ${gamma}$ coactivator-1 ${alpha}$ (PGC-1 ${alpha}$ ) and small heterodimer partnerand an increase in the expression of fibroblast growth factor-19(FGF-19). Ectopic expression of FGF-19 decreases T0-901317-inducedACC ${alpha}$ expression. Inhibition of p38 mitogen-activated proteinkinase (MAPK) and/or extracellular signal-regulated kinase (ERK)suppresses the effects of CDCA on the expression of ACC ${alpha}$ , SREBP-1,PGC-1 ${alpha}$ , and FGF-19. These results demonstrate that CDCA inhibitsT0-901317-induced ACC ${alpha}$ transcription by suppressing the activityof LXR and SREBP-1. We postulate that p38 MAPK, ERK, PGC-1 ${alpha}$ ,and FGF-19 are components of the signaling pathway(s) mediatingthe regulation of ACC ${alpha}$ gene transcription by CDCA. Supplementary key words fatty acid synthesis • sterol-regulatory element binding protein • fibroblast growth factor-19 • peroxisome proliferator-activated receptor ${gamma}$ coactivator-1 ${alpha}$ • p38 mitogen-activated protein kinase • extracellular signal-regulated kinase • small heterodimer partner • farnesoid X receptor