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 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.
Lau
Patrick
P
Institute for Molecular Bioscience, Division of Molecular Genetics and Development, School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia.
Nixon
Susan J
SJ
Parton
Robert G
RG
Muscat
George E O
GE
D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology; D019556:COS Cells; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D051244:Caveolin 3; D022461:Caveolins / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D050881:E1A-Associated p300 Protein; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D005947:Glucose / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D009765:Obesity / Q000473:pathology; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
C495548:Cav3 protein, mouse; D051244:Caveolin 3; D022461:Caveolins; D009687:Nuclear Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; C539738:RORA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D012313:RNA; D002334:Carnitine O-Palmitoyltransferase; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D005982:Glutathione Transferase; D005947:Glucose