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The Peroxisome Proliferator-Activated Receptor β/δ Agonist, GW501516, Regulates the Expression of Genes Involved in Lipid Catabolism and Energy Uncoupling in Skeletal Muscle Cells

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Dressel, Uwe, Allen, Tamara L., Pippal, Jyotsna B., Rohde, Paul R., Lau, Patrick, Muscat, George E. O.·2003·Molecular Endocrinology
DOI 10.1210/me.2003-0151
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Abstract

Lipid homeostasis is controlled by the peroxisome proliferator-activated receptors (PPARalpha, -beta/delta, and -gamma) that function as fatty acid-dependent DNA-binding proteins that regulate lipid metabolism. In vitro and in vivo genetic and pharmacological studies have demonstrated PPARalpha regulates lipid catabolism. In contrast, PPARgamma regulates the conflicting process of lipid storage. However, relatively little is known about PPARbeta/delta in the context of target tissues, target genes, lipid homeostasis, and functional overlap with PPARalpha and -gamma. PPARbeta/delta, a very low-density lipoprotein sensor, is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for approximately 40% of total body weight. Skeletal muscle is a metabolically active tissue, and a primary site of glucose metabolism, fatty acid oxidation, and cholesterol efflux. Consequently, it has a significant role in insulin sensitivity, the blood-lipid profile, and lipid homeostasis. Surprisingly, the role of PPARbeta/delta in skeletal muscle has not been investigated. We utilize selective PPARalpha, -beta/delta, -gamma, and liver X receptor agonists in skeletal muscle cells to understand the functional role of PPARbeta/delta, and the complementary and/or contrasting roles of PPARs in this major mass peripheral tissue. Activation of PPARbeta/delta by GW501516 in skeletal muscle cells induces the expression of genes involved in preferential lipid utilization, beta-oxidation, cholesterol efflux, and energy uncoupling. Furthermore, we show that treatment of muscle cells with GW501516 increases apolipoprotein-A1 specific efflux of intracellular cholesterol, thus identifying this tissue as an important target of PPARbeta/delta agonists. Interestingly, fenofibrate induces genes involved in fructose uptake, and glycogen formation. In contrast, rosiglitazone-mediated activation of PPARgamma induces gene expression associated with glucose uptake, fatty acid synthesis, and lipid storage. Furthermore, we show that the PPAR-dependent reporter in the muscle carnitine palmitoyl-transferase-1 promoter is directly regulated by PPARbeta/delta, and not PPARalpha in skeletal muscle cells in a PPARgamma coactivator-1-dependent manner. This study demonstrates that PPARs have distinct roles in skeletal muscle cells with respect to the regulation of lipid, carbohydrate, and energy homeostasis. Moreover, we surmise that PPARbeta/delta agonists would increase fatty acid catabolism, cholesterol efflux, and energy expenditure in muscle, and speculate selective activators of PPARbeta/delta may have therapeutic utility in the treatment of hyperlipidemia, atherosclerosis, and obesity.

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Research works printed but not linked: 51

  1. Vosper, 2002, Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis., Pharmacol Ther, 95, 47, 10.1016/S0163-7258(02)00232-2 · DOI
  2. Hihi, 2002, PPARs: transcriptional effectors of fatty acids and their derivatives., Cell Mol Life Sci, 59, 790, 10.1007/s00018-002-8467-x · DOI · Paper page
  3. Chawla, 2001, Nuclear receptors and lipid physiology: opening the X-files., Science, 294, 1866, 10.1126/science.294.5548.1866 · DOI · Paper page
  4. Lu, 2001, Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism., J Biol Chem, 276, 37735, 10.1074/jbc.R100035200 · DOI
  5. Berger, 2002, The mechanisms of action of PPARs., Annu Rev Med, 53, 409, 10.1146/annurev.med.53.082901.104018 · DOI · Paper page
  6. Kliewer, 2001, Peroxisome proliferator-activated receptors: from genes to physiology., Recent Prog Horm Res, 56, 239, 10.1210/rp.56.1.239 · DOI · Paper page
  7. Michalik, 2003, Peroxisome proliferator-activated receptors β/δ: emerging roles for a previously neglected third family member., Curr Opin Lipidol, 14, 129, 10.1097/00041433-200304000-00003 · DOI
  8. Peters, 2000, Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor β(δ)., Mol Cell Biol, 20, 5119, 10.1128/MCB.20.14.5119-5128.2000 · DOI
  9. Rosenberger, 2002, Targeted disruption of peroxisomal proliferator-activated receptor β (δ) results in distinct gender differences in mouse brain phospholipid and esterified FA levels., Lipids, 37, 495, 10.1007/s11745-002-0923-1 · DOI
  10. Oliver Jr, 2001, A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport., Proc Natl Acad Sci USA, 98, 5306, 10.1073/pnas.091021198 · DOI · Paper page
  11. Muoio, 2002, Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) α knock-out mice. Evidence for compensatory regulation by PPAR δ., J Biol Chem, 277, 26089, 10.1074/jbc.M203997200 · DOI · Paper page
  12. Son, 2001, Up-regulation of uncoupling protein 3 gene expression by fatty acids and agonists for PPARs in L6 myotubes., Endocrinology, 142, 4189, 10.1210/endo.142.10.8446 · DOI
  13. Hatakeyama, 2001, Transcriptional regulation of uncoupling protein-2 gene expression in L6 myotubes., Int J Obes Relat Metab Disord, 25, 1619, 10.1038/sj.ijo.0801812 · DOI
  14. Chawla, 2003, PPARδ is a very low-density lipoprotein sensor in macrophages., Proc Natl Acad Sci USA, 100, 1268, 10.1073/pnas.0337331100 · DOI · Paper page
  15. Lee, 2003, Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors., Endocrinology, 144, 2201, 10.1210/en.2003-0288 · DOI · Paper page
  16. Muscat, 2002, Regulation of cholesterol homeostasis and lipid metabolism in skeletal muscle by liver X receptors., J Biol Chem, 277, 40722, 10.1074/jbc.M206681200 · DOI
  17. Chen, 1995, A transcriptional co-repressor that interacts with nuclear hormone receptors., Nature, 377, 454, 10.1038/377454a0 · DOI · Paper page
  18. Cabrero, 2002, Increased reactive oxygen species production down-regulates peroxisome proliferator-activated alpha pathway in C2C12 skeletal muscle cells., J Biol Chem, 277, 10100, 10.1074/jbc.M110321200 · DOI
  19. Hunter, 2001, Peroxisome proliferator-activated receptor γ ligands differentially modulate muscle cell differentiation and MyoD gene expression via peroxisome proliferator-activated receptor γ-dependent and -independent pathways., J Biol Chem, 276, 38297, 10.1074/jbc.M103594200 · DOI
  20. Holst, 2003, Nutritional regulation and role of peroxisome proliferator-activated receptor δ in fatty acid catabolism in skeletal muscle., Biochim Biophys Acta, 1633, 43, 10.1016/S1388-1981(03)00071-4 · DOI
  21. Shimokawa, 1998, Transcriptional regulation of muscle-specific genes during myoblast differentiation., Biochem Biophys Res Commun, 246, 287, 10.1006/bbrc.1998.8600 · DOI
  22. Shore, 2002, Oct-2 regulates CD36 gene expression via a consensus octamer, which excludes the co-activator OBF-1., Nucleic Acids Res, 30, 1767, 10.1093/nar/30.8.1767 · DOI
  23. Brandt, 1998, Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor α., J Biol Chem, 273, 23786, 10.1074/jbc.273.37.23786 · DOI · Paper page
  24. Kizaki, 2002, Uncoupling protein 2 plays an important role in nitric oxide production of lipopolysaccharide-stimulated macrophages., Proc Natl Acad Sci USA, 99, 9392, 10.1073/pnas.142206299 · DOI
  25. Wu, 1999, Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1., Cell, 98, 115, 10.1016/S0092-8674(00)80611-X · DOI · Paper page
  26. Michael, 2001, Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1., Proc Natl Acad Sci USA, 98, 3820, 10.1073/pnas.061035098 · DOI · Paper page
  27. Puigserver, 1998, A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis., Cell, 92, 829, 10.1016/S0092-8674(00)81410-5 · DOI · Paper page
  28. Louet, 2002, The coactivator PGC-1 is involved in the regulation of the liver carnitine palmitoyltransferase I gene expression by cAMP in combination with HNF4 α and cAMP-response element-binding protein (CREB)., J Biol Chem, 277, 37991, 10.1074/jbc.M205087200 · DOI
  29. Huss, 2001, Hypoxia inhibits the peroxisome proliferator-activated receptor α/retinoid X receptor gene regulatory pathway in cardiac myocytes: a mechanism for O2-dependent modulation of mitochondrial fatty acid oxidation., J Biol Chem, 276, 27605, 10.1074/jbc.M100277200 · DOI
  30. Barger, 2000, Deactivation of peroxisome proliferator-activated receptor-α during cardiac hypertrophic growth., J Clin Invest, 105, 1723, 10.1172/JCI9056 · DOI · Paper page
  31. Bocher, 2002, PPARs: transcription factors controlling lipid and lipoprotein metabolism., Ann NY Acad Sci, 967, 7, 10.1111/j.1749-6632.2002.tb04258.x · DOI
  32. Duval, 2002, The role of PPARs in atherosclerosis., Trends Mol Med, 8, 422, 10.1016/S1471-4914(02)02385-7 · DOI
  33. Mano, 2000, Cloning and function of rabbit peroxisome proliferator-activated receptor δ/β in mature osteoclasts., J Biol Chem, 275, 8126, 10.1074/jbc.275.11.8126 · DOI
  34. Kelly, 1998, Peroxisome proliferator-activated receptors γ and α mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression., Endocrinology, 139, 4920, 10.1210/endo.139.12.6384 · DOI · Paper page
  35. Wu, 1999, Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes., Diabetes, 48, 1593, 10.2337/diabetes.48.8.1593 · DOI · Paper page
  36. Weigle, 1998, Elevated free fatty acids induce uncoupling protein 3 expression in muscle: a potential explanation for the effect of fasting., Diabetes, 47, 298, 10.2337/diab.47.2.298 · DOI · Paper page
  37. Yoshikawa, 2003, Cross-talk between peroxisome proliferator-activated receptor (PPAR) α and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling., Mol Endocrinol, 17, 1240, 10.1210/me.2002-0190 · DOI · Paper page
  38. Nagai, 2002, Amelioration of high fructose-induced metabolic derangements by activation of PPARα., Am J Physiol Endocrinol Metab, 282, E1180, 10.1152/ajpendo.00471.2001 · DOI
  39. Kim, 2003, Differential effects of rosiglitazone on skeletal muscle and liver insulin resistance in A-ZIP/F-1 fatless mice., Diabetes, 52, 1311, 10.2337/diabetes.52.6.1311 · DOI
  40. Garcia-Martinez, 2001, Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid vs. glucose oxidation., FASEB J, 15, 2033, 10.1096/fj.00-0828fje · DOI
  41. Clapham, 2000, Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean., Nature, 406, 415, 10.1038/35019082 · DOI · Paper page
  42. Zhang, 2001, Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes., Cell, 105, 745, 10.1016/S0092-8674(01)00378-6 · DOI · Paper page
  43. Boss, 1998, Uncoupling protein-3 expression in rodent skeletal muscle is modulated by food intake but not by changes in environmental temperature., J Biol Chem, 273, 5, 10.1074/jbc.273.1.5 · DOI · Paper page
  44. Dulloo, 2001, Uncoupling protein 3 and fatty acid metabolism., Biochem Soc Trans, 29, 785, 10.1042/bst0290785 · DOI
  45. Dulloo, 2001, Uncoupling proteins: their roles in adaptive thermogenesis and substrate metabolism reconsidered., Br J Nutr, 86, 123, 10.1079/BJN2001412 · DOI
  46. Samec, 1998, Role of UCP homologues in skeletal muscles and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate?, FASEB J, 12, 715, 10.1096/fasebj.12.9.715 · DOI · Paper page
  47. Couplan, 2002, High level of uncoupling protein 1 expression in muscle of transgenic mice selectively affects muscles at rest and decreases their IIb fiber content., J Biol Chem, 277, 43079, 10.1074/jbc.M206726200 · DOI
  48. Pilegaard, 2003, Exercise induces transient transcriptional activation of the PGC-1α gene in human skeletal muscle., J Physiol, 546, 851, 10.1113/jphysiol.2002.034850 · DOI · Paper page
  49. Gilde, 2003, Peroxisome proliferator-activated receptor (PPAR) α and PPARβ/δ, but not PPARγ, modulate the expression of genes involved in cardiac lipid metabolism., Circ Res, 92, 518, 10.1161/01.RES.0000060700.55247.7C · DOI · Paper page
  50. Chen, 2000, The steroid receptor coactivator, GRIP-1, is necessary for MEF-2C-dependent gene expression and skeletal muscle differentiation., Genes Dev, 14, 1209, 10.1101/gad.14.10.1209 · DOI
  51. Dressel, 2001, A dynamic role for HDAC7 in MEF2-mediated muscle differentiation., J Biol Chem, 276, 17007, 10.1074/jbc.M101508200 · DOI

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Metadata

Authors
Dressel, U., Allen, T. L., Pippal, J. B., Rohde, P. R., Lau, P., & Muscat, G. E. O.
Venue
Molecular Endocrinology
Publisher
The Endocrine Society
Published
2003-12-01
Volume
17
Issue
12
Pages
2477-2493
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
DOI
10.1210/me.2003-0151
OpenAlex
W2120736359
Cited by
372
References
8
FWCI
8.58
Type
journal article
Language
en
Open access
bronze

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