ROR-alpha's role in lipid metabolism

J Biol Chem. 2004 Aug 27;279(35):36828-36840. Epub 2004 Jun 15. Related
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ROR{alpha} Regulates the Expression of Genes Involved in Lipid
Homeostasis in Skeletal Muscle Cells: CAVEOLIN-3 AND CPT-1 ARE DIRECT
TARGETS OF ROR.

Lau P, Nixon SJ, Parton RG, Muscat GE.

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 RORalpha 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-alpha-lipoproteinemia and
atherosclerosis. However, relatively little is known about RORalpha in
the context of target tissues, target genes, and lipid homeostasis. For
example, RORalpha is abundantly expressed in skeletal muscle, a major
mass peripheral tissue that accounts for approximately 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 RORalpha 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 RORalpha expression in skeletal muscle cells to
understand the regulatory role of RORs in this major mass peripheral
tissue. Exogenous dominant negative RORalpha expression in skeletal
muscle cells represses the endogenous levels of RORalpha and -gamma
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.

PMID: 15199055 [PubMed - as supplied by publisher]