Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Muoio, DM; Way, JM; Tanner, CJ; Winegar, DA; Kliewer, SA; Houmard, JA; Kraus, WE; Dohm, GL

Published Date

  • April 2002

Published In

Volume / Issue

  • 51 / 4

Start / End Page

  • 901 - 909

PubMed ID

  • 11916905

Pubmed Central ID

  • 11916905

International Standard Serial Number (ISSN)

  • 0012-1797

Digital Object Identifier (DOI)

  • 10.2337/diabetes.51.4.901


  • eng

Conference Location

  • United States