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

Deborah M. Muoio, James M. Way, Charles J. Tanner, Deborah A. Winegar, Steven A. Kliewer, Joseph A. Houmard, William E. Kraus, G. Lynis Dohm

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173 Scopus citations

Abstract

In humans, skeletal muscle is a major site of peroxisome proliferator-activated receptor-α (PPAR-α) expression, but its function in this tissue is unclear. We investigated the role of hPPAR-α in regulating muscle lipid utilization by studying the effects of a highly selective PPAR-α agonist, GW7647, on [14C]oleate metabolism and gene expression in primary human skeletal muscle cells. Robust induction of PPAR-α 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 β-oxidation, indicating that PPAR-α-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 ∼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-α in regulating muscle lipid homeostasis.

Original languageEnglish (US)
Pages (from-to)901-909
Number of pages9
JournalDiabetes
Volume51
Issue number4
DOIs
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Muoio, D. M., Way, J. M., Tanner, C. J., Winegar, D. A., Kliewer, S. A., Houmard, J. A., Kraus, W. E., & Lynis Dohm, G. (2002). Peroxisome proliferator-activated receptor-α regulates fatty acid utilization in primary human skeletal muscle cells. Diabetes, 51(4), 901-909. https://doi.org/10.2337/diabetes.51.4.901