Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, 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, CHICK-EMBRYO HEPATOCYTES, ORPHAN NUCLEAR RECEPTOR, BILE-ACID, THYROID-HORMONE, INHIBIT TRANSCRIPTION, DIETARY-CHOLESTEROL, LIPID-METABOLISM, PROTEIN-KINASE, MESSENGER-RNA, MALIC ENZYME, Acetyl-CoA Carboxylase, Animals, Binding Sites, Chenodeoxycholic Acid, Chick Embryo, DNA-Binding Proteins, Hydrocarbons, Fluorinated, Liver X Receptors, Orphan Nuclear Receptors, Receptors, Cytoplasmic and Nuclear, Sterol Regulatory Element Binding Protein 1, Sulfonamides, Transcriptional Activation, p38 Mitogen-Activated Protein Kinases, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics

Abstract:

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 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-CoA carboxylase-alpha (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-gamma coactivator 1-alpha (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 (p38 MAPK) and/or extracellular signal-regulated kinase (ERK) suppresses the effects of CDCA on 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.