1. Academic Validation
  2. Regulation of expression of citrate synthase by the retinoic acid receptor-related orphan receptor α (RORα)

Regulation of expression of citrate synthase by the retinoic acid receptor-related orphan receptor α (RORα)

  • PLoS One. 2012;7(4):e33804. doi: 10.1371/journal.pone.0033804.
Christine Crumbley 1 Yongjun Wang Subhashis Banerjee Thomas P Burris
Affiliations

Affiliation

  • 1 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 α (RORα) 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 RORα 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 RORα response element (RORE) in the promoter of the CS gene. ChIP analysis demonstrates RORα occupancy of the CS promoter and a putative RORE binds to RORα effectively in an electrophoretic mobility shift assay and confers RORα 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 RORα protein. Furthermore, we found that SR1001 a RORα inverse agonist eliminated the circadian pattern of expression of CS mRNA in mice. These data suggest that CS is a direct RORα target gene and one mechanism by which RORα regulates lipid metabolism is via regulation of CS expression.

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