The Chicken Ovalbumin Upstream Promoter-Transcription Factors Modulate Genes and Pathways Involved in Skeletal Muscle Cell Metabolism

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 ∼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 Pparα, Fabp3, and Cpt-1). This was coupled to reduced fatty acid β-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. 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 ∼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 Pparα, Fabp3, and Cpt-1). This was coupled to reduced fatty acid β-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. Nuclear receptors (NRs) 3The abbreviations used are: NR, nuclear receptor; Q-RT, quantitative real time; ABC, ATP-binding cassette proteins; FABP3, fatty acid-binding protein 3; CPT-1, carnitine palmitoyltransferase 1; UCP3, uncoupling protein 3; CYP7A1, cholesterol 7α-hydroxylase; COUP-TF, chicken ovalbumin upstream promoter-transcription factor; LXR, liver X receptor; DMEM, Dulbecco's modified Eagle's medium; siRNA, small interfering RNA; IL, interleukin; PPAR, peroxisome proliferator-activated receptor; PEPCK, phosphoenolpyruvate carboxykinase; DM, differentiation medium. comprise a large family of DNA-binding transcription factors that control many cellular and physiological processes crucial for development and survival. Dysregulation of nuclear receptor signaling leads to proliferative, reproductive, and metabolic disorders such as cancer, infertility, dyslipidemia, and insulin resistance/type II diabetes (1Gronemeyer H. Gustafsson J.A. Laudet V. Nat. Rev. Drug Discov. 2004; 3: 950-964Crossref PubMed Scopus (946) Google Scholar). Consequently, NRs are a major focal point of intense clinical and pharmaceutical studies. The NR superfamily includes receptors for steroid hormones, vitamin D, ecdysone, retinoic acids (all-trans and 9-cis isoforms), and thyroid hormones. In addition to these known receptors for known ligands, there are a number of NRs to which no ligand has been described, and thus, designated “orphan” receptors. Of the orphan nuclear receptors, the chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) have received considerable attention for their role in neurogenesis, organogenesis, and embryogenesis (2Sugiyama T. Wang J.C. Scott D.K. Granner D.K. J. Biol. Chem. 2000; 275: 3446-3454Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 3Cooney A.J. Lee C.T. Lin S.C. Tsai S.Y. Tsai M.J. Trends Endocrinol. Metab. 2001; 12: 247-251Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 4Lee C.T. Li L. Takamoto N. Martin J.F. Demayo F.J. Tsai M.J. Tsai S.Y. Mol. Cell. Biol. 2004; 24: 10835-10843Crossref PubMed Scopus (62) Google Scholar). In mouse there are two highly related Coup-Tfs(Coup-TfI and Coup-TfII) encoded by distinct genes on chromosomes 13 and 7, respectively (5Qiu Y. Krishnan V. Zeng Z. Gilbert D.J. Copeland N.G. Gibson L. Yang-Feng T. Jenkins N.A. Tsai M.J. Tsai S.Y. Genomics. 1995; 29: 240-246Crossref PubMed Scopus (35) Google Scholar). Interestingly, Coup-Tfs can modulate the activity of genes that are fundamental in the orchestration of glucose and lipid metabolism. These include, bile acid synthesis (Cyp7A-cholesterol 7α-hydroxylase) (6Crestani M. Sadeghpour A. Stroup D. Galli G. Chiang J.Y. J. Lipid Res. 1998; 39: 2192-2200Abstract Full Text Full Text PDF PubMed Google Scholar), ketogenesis (mitochondrial hydroxymethylglutaryl-CoA synthase) (7Hegardt F.G. 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In this we the that Coup-Tfs are in the regulation of metabolism. suggest a role for Coup-Tfs in the modulation of genes involved in lipid utilization Fabp3, and and the regulation of total cholesterol and liver X receptor expression of the ATP-binding cassette that control cholesterol (Abca1 and The role of Coup-Tfs in this to lipid utilization and cholesterol in skeletal these processes have for such as mouse were and in with of was by with for RNA and RNA was cells to the RNA was with of for by of the RNA RNA was to the of the was used to of total RNA to the The was to in protein was cells by the addition of were a and for The was and total protein was by the as by the of to the mouse of Coup-TfI was with the target The target was on no with other members of the nuclear receptor family and with The and were and the as by the were by the of of were to and of Coup-TfI and the negative control in the the mouse were in the of as by the was for a and RNA was as of Coup-Tf-siRNA cells were with of and of control in of and of were by with in the and the of the control cell were in with The large number of were and and for were as and were on a and were on a of cell the negative control and the Coup-Tf-siRNA were to and to a of the cells were with LXR agonist, of The cells were for RNA as was on in on RNA levels were in with used for the of target gene have been in A. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). was with of and of for and for The of target gene expression was to RNA as and were the by and on the Nuclear was on the of and a was to protein the negative control and cell was on a and to a The were for in in by with Coup-TfI Abca1 the was with and and for were and by on Coup-Tf-siRNA and the negative control cells were in in to of the promoter J. M. Li J. G. G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google was in the of the cells were with LXR agonist, were the gene as by the was on a J. M. Li J. G. G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ATP total of cells by the the negative control and Coup-Tf-siRNA were and in was and the cells were to for The of ATP was the ATP as by the The are in ATP was to total A was to for cholesterol and cholesterol was as by the cell the negative control and the Coup-Tf-siRNA cells were cells The cells were in and in to the addition of of the LXR agonist, for The cells were in and for to cellular cholesterol a with the was of and of The are in was to total protein and a was to of was on the of the cell culture Coup-Tf-siRNA cells were in for in the Coup-Tf-siRNA cells were for and in of fatty acid fatty of for total of of was with of for by the addition of of and for by for of the was and with of to for on a were as and was a The Coup-TfI and II mRNA and Skeletal the role of Coup-TfI and II in skeletal muscle with to we the expression of both Coup-TfI and II mRNA to in the mouse cell can to and by a This a to a is with activation and repression of a of genes for and the metabolic on this tissue. this of we observed by that both Coup-TfI and II mRNA were skeletal muscle cell differentiation a and the levels of Coup-TfI and differentiation we levels of Coup-TfI and II were observed in the and and to a and the differentiation of the cells and that a and metabolic was on genes a gene that the and is for differentiation S. M. Res. 1995; PubMed Scopus Google Scholar), the and the of the protein and the metabolic genes Abca1 and Abcg1 cassette acid-binding protein palmitoyltransferase and protein the of differentiation and the protein genes and and were the and the of the cell Furthermore, the expression of these of differentiation are with A. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. S. Res. 1998; PubMed Scopus Google Scholar). genes involved in lipid metabolism and and energy were skeletal and that the muscle cells a metabolic to the of Abca1, we the levels of this protein the these the Abca1 protein with the Abca1 mRNA Coup-Tf-siRNA of Coup-TfI and mRNA and in Skeletal the role of Coup-Tfs in skeletal muscle with to lipid we to the expression of Coup-TfI and II. RNA was to cell Coup-Tf-siRNA no to other nuclear in to mRNA levels of both Coup-TfI and II. a control we cells the negative control in the cell the negative control and the were for and total RNA and protein was of the and are for the negative control and the Coup-Tf-siRNA cells. negative and the Coup-Tf-siRNA cell a to a of a was to the expression of both Coup-TfI and mRNA to both and in the RNA the negative control and Coup-Tf-siRNA-transfected cell We observed a significant attenuation of both the Coup-TfI and mRNA with the negative control and to and Moreover, the expression of Coup-TfI and II mRNA was to and and that the attenuation of both Coup-TfI and II mRNA was to mRNA was on mRNA to was observed in the levels of mRNA expression in the negative control to the Coup-Tf-siRNA cell and thus, the expression of Coup-TfI and II mRNA in the Coup-Tf-siRNA the repression of Coup-TfI and mRNA expression with protein was Coup-TfI and II both Coup-TfI and II were reduced in the Coup-Tf-siRNA to the negative control and The of attenuation by the to the negative were by the expression of both Coup-TfI and II mRNA of the cells were with the negative control and Coup-Tf-siRNA and the levels of both Coup-TfI and II mRNA were in Coup-TfI and II mRNA were in the Coup-Tf-siRNA Moreover, these data that the attenuation of both Coup-TfI and II is a of the for the of cell and is to the expression of the of Coup-Tf-siRNA the of in Lipid involved in lipid utilization lipid and for and were and a and Consequently, we these in gene expression on lipid in these cells a In with the attenuation of we observed reduced fatty acid in the Coup-Tf-siRNA to the negative cells A number of other genes in fatty acid homeostasis were were observed the negative control and the Coup-Tf-siRNA expression of genes involved in energy and expression expression as number of expression expression as number of and and and acid homeostasis homeostasis expression as number of and in a We a number of nuclear receptors that are of lipid metabolism and for and J. 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We observed a attenuation of phosphoenolpyruvate a gene involved in was in Coup-Tf-siRNA cells genes involved in and glucose homeostasis were were observed and The of Coup-TfI and II the of the and ATP we the the uncoupling and other genes involved in energy and the expression of genes and that are involved in energy uncoupling and lipid were significantly mRNA was (and in mRNA expression was in the Coup-Tf-siRNA cell a and and other genes involved in energy and were significantly in this the of the attenuation of mRNA in the Coup-Tf-siRNA cell we and the levels of ATP in the negative control and Coup-Tf-siRNA-transfected cells. In with the reduction of mRNA expression in the Coup-Tf-siRNA we observed 5-fold increase in ATP levels in the Coup-Tf-siRNA to the negative control cells of the Coup-Tfs the of in (Abca1 and a number of genes in lipid We observed the the reverse cholesterol Abca1 and were both significantly and and The of on Lipid of the observed in the Coup-Tf-siRNA cell were to the mRNA levels of the differentiation and and were in the RNA both the negative and the Coup-Tf-siRNA cell in the expression of the mRNA and were observed with the negative control to the significant observed in the metabolic genes Moreover, and we observed both and repression and Abca1, and of genes in the cells that are the differentiation and These data that the observed are and that the of attenuation on metabolism were to on of and genes expression as number of and expression as number of and in a Furthermore, to that the attenuation of and the modulation of metabolic genes was of the we on these genes cells with the In these we observed modulation of these genes Pparα, Abca1, and the observed in the Coup-Tf-siRNA cells was to the cell of Coup-TfI and II of Abca1, and mRNA observed that of Coup-TfI and II mRNA expression the expression of “classical” target genes Abca1, and we the and signaling in skeletal muscle cells and the of expression on Consequently, we the negative control and the Coup-Tf-siRNA-transfected cell with and the LXR agonist, and the activation of LXR target of the negative control cells resulted in a activation of the LXR target genes Abca1, and and to the and as J. M. Li J. G. G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the repression of the of Abca1, and These in the of significant in and mRNA expression and has been that activation of Lxr-dependent Abca1 and Abcg1 expression reverse cholesterol and intracellular cholesterol In this we observed of the Lxr-dependent activation of Abca1 and Abcg1 mRNA we the of the selective LXR agonist, on total intracellular cholesterol levels in the negative control and the Coup-Tf-siRNA-transfected cells. we observed a significant reduction in total intracellular cholesterol in negative control cells. In the LXR intracellular cholesterol levels in the Coup-Tf-siRNA-transfected cell 7, a and This with the of Abca1 and Abcg1 mRNA expression in the Coup-Tf-siRNA-transfected cell of Coup-TfI and II mRNA the Lxr-mediated of the we the attenuation of the activity of the to the activity of the Lxr-dependent promoter in the negative control cells. In to the promoter in the Coup-Tf-siRNA-transfected cells This the of Coup-Tfs on expression are by COUP-TFs are members of the orphan nuclear receptor superfamily that are in and COUP-TFs regulate genes involved in cholesterol fatty acid and However, the role of COUP-TFs with to the control of with metabolism in skeletal muscle other major mass peripheral has been we have siRNA-mediated of Coup-TfI and II to the Coup-Tfs regulate of metabolism in skeletal muscle cells. We the mouse skeletal muscle cell culture model as data this in model with LXR and J. M. Li J. G. G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google were in in mouse T. J. S. H. H. Y. M. Y. Y. H. S. T. T. M. J. M. T. J. S. A. PubMed Scopus Google Scholar, J. H. Biol. 2004; PubMed Scopus Google Scholar). The Coup-TfI and II are skeletal muscle In protein levels are as the the cell and This that cell that is by control this the and is However, of Coup-TfI are as RNA in the a site of regulation A. A. D. Biol. 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In this the Coup-Tf-siRNA cells significantly levels of total ATP to the negative control cells. This with the reduction of mRNA expression in these cells. these of in cells a reduction in ATP levels J. J.A. J. PubMed Google Scholar). We that is in tissue. However, have mRNA expression is in skeletal muscle cells T. M. S. Res. 1998; PubMed Scopus Google Scholar, S. L. J. Metab. 2004; 24: PubMed Scopus Google and that expression in muscle in a is in the of the mouse G. S. A. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), a with to muscle is highly in skeletal in contrast to the role of in β-oxidation energy the role of the is and of in and in cell culture S. A. J.C. Metab. PubMed Scopus Google Scholar, 2004; PubMed Scopus Google Scholar, G. F. J. 2001; PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar, L. R. J. PubMed Scopus Google suggest that is involved in and lipid utilization. that repression of Coup-Tfs leads to a significant increase in mRNA a in the of reduced Fabp3, and of has been as a to the attenuation of expression in a model Y. Wang Y. M. T. Wang Z. Y. N. H. Cell. PubMed Scopus Google Scholar). this in a role in the the expression of the target is in the skeletal muscle of Li S. J.A. J.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These are in with The observed significant repression of LXR target genes involved in reverse cholesterol and and in the Coup-Tf-siRNA-transfected cells is of for has been to the cholesterol (6Crestani M. Sadeghpour A. Stroup D. Galli G. Chiang J.Y. J. Lipid Res. 1998; 39: 2192-2200Abstract Full Text Full Text PDF PubMed Google Scholar, D. Chiang J.Y. J. Lipid Res. 2000; Full Text Full Text PDF PubMed Google Scholar), and the cholesterol ester transfer protein gene (8Gaudet F. Ginsburg G.S. J. Biol. 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T. PubMed Scopus Google expression by the selective LXR agonist, of major in and Moreover, this was with no in intracellular cholesterol levels in the Coup-Tf-siRNA cell contrast to the negative with the LXR In in the gene have been to these have a to cholesterol and cellular cholesterol J. A. Kelly A. S. Wang J. G. PubMed Scopus Google Scholar). has been that a in mouse liver of genes involved in both fatty acid and synthesis A. L. Gustafsson J.A. J.C. Mol. 2004; PubMed Scopus Google Scholar). This in cell model the of and attenuation in the modulation of genes involved in metabolism. A number of have a role for Coup-Tfs in cholesterol metabolism. was to the of the and gene J.A. M. D. J. V. J. Biol. Chem. Full Text PDF PubMed Google Scholar). These are major of the and are for their role in cholesterol to the liver for and in the of bile Moreover, are with the of The of to modulate gene expression involved in cholesterol homeostasis have in the small are in the of cholesterol In these the and cholesterol in skeletal muscle are with other on Lxr-mediated gene regulation and cholesterol homeostasis in other major mass Moreover, these the role of Coup-Tfs in skeletal muscle lipid utilization and and a to the involved in control of cholesterol are to the role of these orphan NRs in We and for with