RORα Regulates the Expression of Genes Involved in Lipid Homeostasis in Skeletal Muscle Cells

Abstract

The staggerer mice carry a deletion in the ROR gene and have a prolonged humoral response, overproduce inflammatory cytokines, and are immunodeficient. Furthermore , the staggerer mice display lowered plasma apoA-I/-II, decreased plasma high density lipoprotein cholesterol and triglycerides, and develop hypo-li-poproteinemia and atherosclerosis. However, relatively little is known about ROR in the context of target tissues , target genes, and lipid homeostasis. For example, ROR is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for 40% of total body weight and 50% of energy expenditure. This lean tissue is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. In particular, the role of ROR in skeletal muscle metabolism has not been investigated, and the contribution of skeletal muscle to the ROR/ phenotype has not been resolved. We utilize ectopic dominant negative ROR expression in skeletal muscle cells to understand the regulatory role of RORs in this major mass peripheral tissue. Exogenous dominant negative ROR expression in skeletal muscle cells represses the endog-enous levels of ROR and-mRNAs and ROR-dependent gene expression. Moreover, we observed attenuated expression of many genes involved in lipid homeostasis. Furthermore, we show that the muscle carnitine palmi-toyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid home-ostasis in skeletal muscle. In conclusion, we speculate that ROR agonists would increase fatty acid catabolism in muscle and suggest selective activators of ROR may have therapeutic utility in the treatment of obesity and atherosclerosis. Members of the nuclear hormone receptor (NR) 1 superfamily bind specific DNA elements and function as transcriptional regulators (1, 2). This group includes the "orphan NRs," which have no known ligands in the "classical sense." The orphan receptor, ROR/RZR (retinoic acid receptor-related orphan receptor), is closely related to Rev-erbA, RVR/Rev-erb/BD73, and the Drosophila orphan receptor, E75A, particularly in the DNA-binding domain and the putative ligand-binding domain. ROR, Rev-erbA, and RVR bind as monomers to an asymmetric (A/T) 6 RGGTCA motif. ROR functions as a constitutive trans-activator of gene expression, and in contrast, Rev-erbA and RVR do not activate transcription, mediate transcriptional repression , and can repress constitutive trans-activation from this motif by ROR (3-9).