Analysis of the mechanisms mediating the regulation of acetyl -CoA carboxylase transcription by the liver X receptor and chenodeoxycholic acid

Agonists of the liver X receptor (LXR) prevent and decrease arterial plaque formation in experimental models of atherosclerosis. The anti-atherosclerotic effects of LXR agonists are mediated by an increase in expression of genes involved in cholesterol export. Currently, the therapeutic utility of LXR agonists is limited by the fact that these agents increase triglyceride levels in the blood and liver. These undesired effects are caused by an increase in transcription of genes controlling triglyceride synthesis, such as acetyl CoA carboxylasealpha (ACCalpha). We have demonstrated that a synthetic LXR agonist, T0-901317 increases ACCalpha via both a direct mechanism involving the activation of LXR/retinoid X receptor (RXR) heterodimers on the ACCalpha gene and by an indirect mechanism involving the increased expression of sterol regulatory element binding protein-1 (SREBP-1). SREBP-1 binds a site adjacent to the ACCalpha LXRE and enhances the ability of LXR/RXR to activate ACCalpha transcription. We screened a number of compounds for their ability to inhibit the stimulatory effects of T0-901317 on expression of lipogenic genes in primary cultures of hepatocytes. We found that the bile acid, chenodeoxycholic acid (CDCA), inhibited the T0-901317-induced increase in mRNA abundance encoding ACCalpha, fatty acid synthase, and stearoyl CoA desaturase-1. CDCA also blocked the stimulatory effects of T0-901317 on triglyceride secretion into the culture medium. Results from transient transfection analyses identified two cis-acting elements that mediated the inhibitory effects of CDCA on T0-901317-induced ACCalpha transcription. One element bound LXR/RXR heterodimers and the other element bound SREBP-1. Treatment with CDCA decreased the expression of mature, active SREBP-1 and decreased the binding of LXR/RXR heterodimers to the ACCalpha promoter. Further studies demonstrated that the CDCA-mediated inhibition of ACCalpha transcription was associated with an activation of extracellular signal-related kinase-1/2 (ERK1/2) and p38 mitogen activated protein kinase (p38MAPK) and that inhibitors of ERK1/2 and p38MAPK abolished or substantially attenuated the inhibitory effect of CDCA on ACCalpha expression. These results indicate that CDCA inhibits T0-901317-induced ACCalpha expression by decreasing the transcriptional activity of LXR and SREBP-1 and that ERK1/2 and p38MAPK are components of the signaling pathway mediating the inhibitory effects of CDCA on ACCalpha expression and triglyceride secretion