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RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR.
J Biol Chem. 2004 Aug 27; 279(35):36828-40.JB

Abstract

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.

Authors+Show Affiliations

Institute for Molecular Bioscience, Division of Molecular Genetics and Development, School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15199055

Citation

Lau, Patrick, et al. "RORalpha Regulates the Expression of Genes Involved in Lipid Homeostasis in Skeletal Muscle Cells: Caveolin-3 and CPT-1 Are Direct Targets of ROR." The Journal of Biological Chemistry, vol. 279, no. 35, 2004, pp. 36828-40.
Lau P, Nixon SJ, Parton RG, et al. RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. J Biol Chem. 2004;279(35):36828-40.
Lau, P., Nixon, S. J., Parton, R. G., & Muscat, G. E. (2004). RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. The Journal of Biological Chemistry, 279(35), 36828-40.
Lau P, et al. RORalpha Regulates the Expression of Genes Involved in Lipid Homeostasis in Skeletal Muscle Cells: Caveolin-3 and CPT-1 Are Direct Targets of ROR. J Biol Chem. 2004 Aug 27;279(35):36828-40. PubMed PMID: 15199055.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. AU - Lau,Patrick, AU - Nixon,Susan J, AU - Parton,Robert G, AU - Muscat,George E O, Y1 - 2004/06/15/ PY - 2004/6/17/pubmed PY - 2004/10/7/medline PY - 2004/6/17/entrez SP - 36828 EP - 40 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 279 IS - 35 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15199055/RORalpha_regulates_the_expression_of_genes_involved_in_lipid_homeostasis_in_skeletal_muscle_cells:_caveolin_3_and_CPT_1_are_direct_targets_of_ROR_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15199055 DB - PRIME DP - Unbound Medicine ER -