The mechanism mediating the activation of acetyl-coenzyme A carboxylase-α gene transcription by the liver X receptor agonist T0-901317

Abstract

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-α (ACCα) gene in chick embryo hepatocyte cultures. Transfection analyses demonstrate that activation of ACCα transcription by T0-901317 is mediated by a cis-acting regulatory unit (−101 to −71 bp) that is composed of a liver X receptor response element (LXRE) and a sterol-regulatory element (SRE). The SRE enhances the ability of the LXRE to activate ACCα transcription in the presence of T0-901317. Treating hepatocytes with T0-901317 increases the concentration of mature sterol-regulatory element binding protein-1 (SREBP-1) in the nucleus and the acetylation of histone H3 and histone H4 at the ACCα LXR response unit. These results indicate that T0-901317 increases hepatic ACCα transcription by directly activating LXR•retinoid X receptor (RXR) heterodimers and by increasing the activity of an accessory transcription factor (SREBP-1) that enhances ligand induced-LXR•RXR activity.

Keywords

• fatty acid synthesis
• sterol-regulatory element binding protein
• thyroid hormone
• chicken
• histone acetylation