Metabolic diseases associated with aberrant metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality in older people in Western Society. Several members of the nuclear receptor superfamily regulate the expression of key genes involved in regulation of carbohydrate and lipid metabolism in response to their ligands, which include fatty acids, bile acids, cholesterol metabolites, steroid hormones, and lipophilic vitamin derivatives. Recently, the ligand for a pair of related orphan nuclear hormone receptors that regulate lipid metabolism, rev-erb? and rev-erb?, was identified. The long term objective is to determine the role of this ligand, the porphyrin heme, in regulation of the activity of the rev-erbs. Our organizing hypothesis is: heme is a key ligand regulating rev-erb?/? function in regulation of genes controlling lipid metabolism and differentiation by modulating the receptors'affinity for corepressors. The hypothesis will be tested in the following specific aims:
Specific Aim 1 will determine the effect of heme on rev-erb corepressor recruitment and regulation of transcription and differentiation.
Specific Aim 2 will determine the specificity of heme for rev-erb?/rev-erb? using biochemical and cell-based approaches.
Specific Aim 3 will determine if heme is utilized as a sensor conveying nutritional status information to rev-erbs so that they may adjust the expression key genes involved in lipid metabolism and adipogenesis. These studies are essential for our understanding how ligands may coordinate rev-erb regulated metabolism, and more generally, how metabolic pathways are regulated by the external environment such as nutrient status. Since nuclear hormone receptors characterized as ligand-regulated have been definitively shown to be effective targets for the development of pharmaceuticals, we predict that our proposed studies may provide the basis for novel therapeutics targeting rev-erb? and rev-erb? for treatment of metabolic disorders. Metabolic diseases associated with aberrant metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality in older people in Western Society. We propose to characterize the role of a novel ligand, the porphyrin heme, in regulation of rev-erb? and rev-erb? ? two orphan nuclear hormone receptors that regulate the expression of key genes involved in lipid metabolism. Since nuclear hormone receptors characterized as ligand-regulated have been definitively shown to be effective targets for the development of pharmaceuticals, we predict that our proposed studies may provide the basis for novel therapeutics targeting rev-erb? and rev-erb? for treatment of metabolic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080201-06
Application #
8249447
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$388,120
Indirect Cost
$192,100
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Busby, Scott A; Kumar, Naresh; Kuruvilla, Dana S et al. (2011) Identification of a novel non-retinoid pan inverse agonist of the retinoic acid receptors. ACS Chem Biol 6:618-27

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