regulation of expression of citrate synthase by the retinoic acid receptor-related orphan receptor α (rorα)柠檬酸合成酶的表达调节视黄酸受体相关孤儿受体α(rorα).pdfVIP

Regulation of Expression of Citrate Synthase by the Retinoic Acid Receptor-Related Orphan Receptor a (RORa) Christine Crumbley, Yongjun Wang, Subhashis Banerjee, Thomas P. Burris* Department of Molecular Therapeutics and Center for Diabetes and Metabolic Disease, The Scripps Research Institute, Jupiter, Florida, United States of America Abstract The retinoic acid receptor-related orphan receptor a (RORa) is a member of the nuclear receptor superfamily of transcription factors that plays an important role in regulation of the circadian rhythm and metabolism. Mice lacking a functional RORa display a range of metabolic abnormalities including decreased serum cholesterol and plasma triglycerides. Citrate synthase (CS) is a key enzyme of the citric acid cycle that provides energy for cellular function. Additionally, CS plays a critical role in providing citrate derived acetyl-CoA for lipogenesis and cholesterologenesis. Here, we identified a functional RORa response element (RORE) in the promoter of the CS gene. ChIP analysis demonstrates RORa occupancy of the CS promoter and a putative RORE binds to RORa effectively in an electrophoretic mobility shift assay and confers RORa responsiveness to a reporter gene in a cotransfection assay. We also observed a decrease in CS gene expression and CS enzymatic activity in the staggerer mouse, which has a mutation of in the Rora gene resulting in nonfunctional RORa protein. Furthermore, we found that SR1001 a RORa inverse agonist eliminated the circadian pattern of expression of CS mRNA in mice. These data suggest that CS is a direct RORa target gene and one mechanism by which RORa regulates lipid metabolism is via regulation of CS expression. Citation: Crumbley C, Wang Y, Banerjee S, Burris TP (2012) Regulation of Expression of Citrate Synthase by the Retinoic Acid Recepto