Chenodeoxycholic acid suppresses the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317.
نویسندگان
چکیده
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-alpha (ACCalpha) and other lipogenic enzymes in chick embryo hepatocyte cultures. CDCA inhibits T0-901317-induced ACCalpha 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 ACCalpha LXR response unit. The CDCA-mediated reduction in ACCalpha expression is associated with a decrease in the expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) 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 ACCalpha 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 ACCalpha, SREBP-1, PGC-1alpha, and FGF-19. These results demonstrate that CDCA inhibits T0-901317-induced ACCalpha transcription by suppressing the activity of LXR and SREBP-1. We postulate that p38 MAPK, ERK, PGC-1alpha, and FGF-19 are components of the signaling pathway(s) mediating the regulation of ACCalpha gene transcription by CDCA.
منابع مشابه
The mechanism mediating the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317.
In birds and mammals, agonists of the liver X receptor (LXR) increase the expression of enzymes that make up the fatty acid synthesis pathway. Here, we investigate the mechanism by which the synthetic LXR agonist, T0-901317, increases the transcription of the acetyl-coenzyme A carboxylase-alpha (ACC alpha) gene in chick embryo hepatocyte cultures. Transfection analyses demonstrate that activati...
متن کاملLiver X receptor activation stimulates insulin secretion via modulation of glucose and lipid metabolism in pancreatic beta-cells.
Liver X receptors (LXRs) alpha and beta, transcription factors of a nuclear hormone receptor family, are expressed in pancreatic islets as well as glucagon-secreting and insulin-secreting cell lines. Culture of pancreatic islets or insulin-secreting MIN6 cells with a LXR specific agonist T0901317 caused an increase in glucose-dependent insulin secretion and islet insulin content. The stimulator...
متن کاملGenetic Polymorphism Detection of the Exon 1 Region of Acetyl-CoA Carboxylase Alpha Gene in Iranian Mahabadi Goat Breed
Acetyl-coenzyme A carboxylase α (ACC-alpha) is considered as the key regulatory enzyme in fatty acid biosynthesis. ACC-alpha gene is located on Caprine chromosome 11 and is polymorphic in many goat breeds. In the current study, we aimed to find possible single nucleotide polymorphisms (SNPs) in the exon 1 region of the ACC-alpha gene in Iranian Mahabadi goat breed. Genomic DNA was extracted fro...
متن کاملAnti-atherosclerotic effect of Farnesoid-X-Receptor in ApoE mice
Abbreviations: acetyl-CoA carboxylase (ACC); acetyl-CoA synthetase (AceCS); carnitine palmitoyltransferase I (CPT-I); chenodeoxycholic acid (CDCA); cholesterol 7 hydroxylase (CYP7A1); cholic acid (CA); farnesoid X receptor (FXR); fatty acid synthase (FAS); LDL receptor (LDL-R); INT-747, 6ethyl-CDCA; liver X receptor (LXR; long-chain acyl-CoA dehydrogenase (LCAD); malic enzyme (ME); medium-chain...
متن کاملLiver X Receptor Agonist TO901317 Prevents Diacylglycerols Accumulation in the Heart of Streptozotocin-Diabetic Rats.
BACKGROUND/AIMS Liver X receptors (LXRα and LXRβ) are ligand-activated transcription factors that regulate expression of genes involved in lipid and cholesterol metabolism. LXR expression has been identified in the heart, and enhanced LXR activity in the streptozotocin (STZ) diabetic myocardium was reported recently. The aim of this study was to investigate effect of in vivo LXR activation on m...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Journal of lipid research
دوره 48 12 شماره
صفحات -
تاریخ انتشار 2007