title: The chicken ovalbumin upstream promoter-transcription factors modulate genes and pathways involved in skeletal muscle cell metabolism.
abstract: The chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) are "orphan" members of the nuclear hormone receptor (NR) superfamily. COUP-TFs are involved in organogenesis and neurogenesis. However, their role in skeletal muscle (and other major mass tissues) and metabolism remains obscure. Skeletal muscle accounts for approximately 40% of total body mass and energy expenditure. Moreover, this peripheral tissue is a primary site of glucose and fatty acid utilization. We utilize small interfering RNA (siRNA)-mediated attenuation of Coup-TfI and II (mRNA and protein) in a skeletal muscle cell culture model to understand the regulatory role of Coup-Tfs in this energy demanding tissue. This targeted NR repression resulted in the significant attenuation of genes that regulate lipid mobilization and utilization (including Pparalpha, Fabp3, and Cpt-1). This was coupled to reduced fatty acid beta-oxidation. Additionally we observed significant attenuation of Ucp1, a gene involved in energy expenditure. Concordantly, we observed a 5-fold increase in ATP levels in cells with siRNA-mediated repression of Coup-TfI and II. Furthermore, the expression of "classical" liver X receptor (LXR) target genes involved in reverse cholesterol transport (Abca1 and Abcg1) were both significantly repressed. Moreover, we observed that repression of the Coup-Tfs ablated the activation of Abca1, and Abcg1 mRNA expression by the selective LXR agonist, T0901317. In concordance, Coup-Tf-siRNA-transfected cells were refractory to Lxr-mediated reduction of total intracellular cholesterol levels in contrast to the negative control cells. In agreement Lxr-mediated activation of the Abca1 promoter in Coup-Tf-siRNA cells was attenuated. Collectively, these data suggest a pivotal role for Coup-Tfs in the regulation of lipid utilization/cholesterol homeostasis in skeletal muscle cells and the modulation of Lxr-dependent gene regulation.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia. s.myers@imb.uq.edu.au
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Myers
authors.forename: S-C Mary
authors.initials: SC
authors.lastname: Wang
authors.forename: George E O
authors.initials: GE
authors.lastname: Muscat
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D051836:COUP Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated; D050356:Lipid Metabolism / Q000235:genetics; D008074:Lipoproteins / Q000235:genetics; D000071518:Liver X Receptors; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D051836:COUP Transcription Factors; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C487540:ABCG1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides