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

Academic Article


  • 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-α (ACCα) and other lipogenic enzymes in chick embryo hepatocyte cultures. CDCA inhibits T0-901317-induced ACCα transcription by suppressing the enhancer activity of a LXR response unit (2101 to 271 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 ACCα LXR response unit. The CDCA-mediated reduction in ACCα expression is associated with a decrease in the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) 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 ACCα 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 ACCa, SREBP-1, PGC-1α, and FGF-19.jlr These results demonstrate that CDCA inhibits T0-901317-induced ACCα transcription by suppressing the activity of LXR and SREBP-1. We postulate that p38 MAPK, ERK, PGC-1α, and FGF-19 are components of the signaling pathway(s) mediating the regulation of ACCα gene transcription by CDCA. Copyright © 2007 by the American Society for Biochemistry and Molecular Biology, Inc.
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    Author List

  • Talukdar S; Bhatnagar S; Dridi S; Hillgartner FB
  • Start Page

  • 2647
  • End Page

  • 2663
  • Volume

  • 48
  • Issue

  • 12