Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells.
In humans, skeletal muscle is a major site of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) expression, but its function in this tissue is unclear. We investigated the role of hPPAR-alpha in regulating muscle lipid utilization by studying the effects of a highly selective PPAR-alpha agonist, GW7647, on [(14)C]oleate metabolism and gene expression in primary human skeletal muscle cells. Robust induction of PPAR-alpha protein expression occurred during muscle cell differentiation and corresponded with differentiation-dependent increases in oleate oxidation. In mature myotubes, 48-h treatment with 10-1,000 nmol/l GW7647 increased oleate oxidation dose-dependently, up to threefold. Additionally, GW7647 decreased oleate esterification into myotube triacylglycerol (TAG), up to 45%. This effect was not abolished by etomoxir, a potent inhibitor of beta-oxidation, indicating that PPAR-alpha-mediated TAG depletion does not depend on reciprocal changes in fatty acid catabolism. Consistent with its metabolic actions, GW7647 induced mRNA expression of mitochondrial enzymes that promote fatty acid catabolism; carnitine palmityltransferase 1 and malonyl-CoA decarboxylase increased approximately 2-fold, whereas pyruvate dehydrogenase kinase 4 increased 45-fold. Expression of several genes that regulate glycerolipid synthesis was not changed by GW7647 treatment, implicating involvement of other targets to explain the TAG-depleting effect of the compound. These results demonstrate a role for hPPAR-alpha in regulating muscle lipid homeostasis.
Muoio
Deborah M
DM
Department of Medicine and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. muoio@duke.edu
Way
James M
JM
Tanner
Charles J
CJ
Winegar
Deborah A
DA
Kliewer
Steven A
SA
Houmard
Joseph A
JA
Kraus
William E
WE
Dohm
G Lynis
GL
D002087:Butyrates / Q000494:pharmacology*; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008858:Microscopy, Phase-Contrast; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism*
D002087:Butyrates; D004268:DNA-Binding Proteins; D005230:Fatty Acids, Nonesterified; C453899:GW 7647; D010671:Phenylurea Compounds; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D019301:Oleic Acid; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase