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-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.
Highlights
In birds and mammals, agonists of the liver X receptor (LXR) increase the expression of enzymes that make up the fatty acid synthesis pathway
Oral administration of T0-901317 to chickens and rats causes a 2- to 3-fold increase in hepatic ACCa mRNA levels [25, 26]. To investigate whether this phenomenon was attributable to a direct effect of T0-901317 in the liver, we determined whether T0-901317 regulated the expression of ACCa in primary cultures of chick embryo hepatocytes
In our studies analyzing the regulation of the ACCa gene by T3, we showed that T3 treatment increased the abundance of the mature, active form of sterol-regulatory element binding protein1 (SREBP-1) in chick embryo hepatocytes and that this effect contributed to the activation of ACCa transcription by T3 [8]
Summary
Agonists of the liver X receptor (LXR) increase the expression of enzymes that make up the fatty acid synthesis pathway. We investigate the mechanism by which the synthetic LXR agonist, T0-901317, increases the transcription of the acetyl-coenzyme A carboxylase-a (ACCa) gene in chick embryo hepatocyte cultures. Treating hepatocytes with T0-901317 increases the concentration of mature sterol-regulatory element binding protein (SREBP-1) in the nucleus and the acetylation of histone H3 and histone H4 at the ACCa LXR response unit. These results indicate that T0-901317 increases hepatic ACCa 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, S., and F. This article is available online at http://www.jlr.org
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