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 activation of ACC alpha 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 ACC alpha 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 ACC alpha LXR response unit. These results indicate that T0-901317 increases hepatic ACC alpha 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.
Talukdar
Saswata
S
Department of Biochemistry and Molecular Pharmacology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA.
Hillgartner
F Bradley
FB
D000103:Acetyl-CoA Carboxylase / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010957:Plasmids / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000103:Acetyl-CoA Carboxylase; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides