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J. Biol. Chem., Vol. 279, Issue 35, 36828-36840, August 27, 2004
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ROR
Regulates the Expression of Genes Involved in Lipid Homeostasis in Skeletal Muscle Cells
CAVEOLIN-3 AND CPT-1 ARE DIRECT TARGETS OF ROR*
¶¶||**||
From the
Institute for Molecular Bioscience, Division of Molecular Genetics and Development, ¶Centre for Microscopy and Microanalysis, School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia
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--lipoproteinemia 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 endogenous 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 palmitoyltransferase-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 homeostasis 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.
Received for publication, May 4, 2004 , and in revised form, June 8, 2004.
* This work was supported in part by a National Health and Medical Research Council of Australia project grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| Principal Research Fellow of the National Health and Medical Research Council of Australia.
** Supported by the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia.
To whom correspondence should be addressed. Tel.: 61-7-3346-2039; E-mail: g.muscat{at}imb.uq.edu.au.
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