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Journal of Lipid Research, Vol. 48, 2647-2663, December 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Chenodeoxycholic acid suppresses the activation of acetyl-coenzyme A carboxylase- gene transcription by the liver X receptor agonist T0-901317

Saswata Talukdar, Sushant Bhatnagar, Sami Dridi and F. Bradley Hillgartner¹

Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, WV 26506

Published, JLR Papers in Press, September 6, 2007.

¹ To whom correspondence should be addressed. e-mail: fbhillgartner{at}hsc.wvu.edu

The therapeutic utility of liver X receptor (LXR) agonists in treating atherosclerosis is limited by an undesired accumulation of triglycerides in the blood and liver. This effect is caused by an increase in the transcription of genes involved in fatty acid synthesis. Here, we show that the primary bile acid, chenodeoxycholic acid (CDCA), antagonizes the stimulatory effect of the synthetic LXR agonist, T0-901317, on the expression of acetyl-coenzyme A carboxylase- (ACC) and other lipogenic enzymes in chick embryo hepatocyte cultures. CDCA inhibits T0-901317-induced ACC transcription by suppressing the enhancer activity of a LXR response unit (–101 to –71 bp) that binds LXR and sterol-regulatory element binding protein-1 (SREBP-1). We also demonstrate that CDCA decreases the expression of SREBP-1 in the nucleus and the acetylation of histone H3 and H4 at the ACC LXR response unit. The CDCA-mediated reduction in ACC expression is associated with a decrease in the expression of peroxisome proliferator-activated receptor coactivator-1 (PGC-1) and small heterodimer partner and an increase in the expression of fibroblast growth factor-19 (FGF-19). Ectopic expression of FGF-19 decreases T0-901317-induced ACC expression. Inhibition of p38 mitogen-activated protein kinase (MAPK) and/or extracellular signal-regulated kinase (ERK) suppresses the effects of CDCA on the expression of ACC, SREBP-1, PGC-1, and FGF-19. These results demonstrate that CDCA inhibits T0-901317-induced ACC transcription by suppressing the activity of LXR and SREBP-1. We postulate that p38 MAPK, ERK, PGC-1, and FGF-19 are components of the signaling pathway(s) mediating the regulation of ACC gene transcription by CDCA.

Supplementary key words fatty acid synthesis • sterol-regulatory element binding protein • fibroblast growth factor-19 • peroxisome proliferator-activated receptor coactivator-1 • p38 mitogen-activated protein kinase • extracellular signal-regulated kinase • small heterodimer partner • farnesoid X receptor

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