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

被引:188
作者
Muoio, DM
Way, JM
Tanner, CJ
Winegar, DA
Kliewer, SA
Houmard, JA
Kraus, WE
Dohm, GL
机构
[1] Duke Univ, Med Ctr, Dept Med & Cell Biol, Durham, NC 27710 USA
[2] GlaxoSmithKline, Dept Mol Endocrinol, Res Triangle Pk, NC USA
[3] GlaxoSmithKline, Dept Metab Dis, Res Triangle Pk, NC USA
[4] E Carolina Univ, Dept Biochem, Greenville, NC USA
[5] E Carolina Univ, Human Performance Lab, Greenville, NC USA
关键词
D O I
10.2337/diabetes.51.4.901
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 [C-14]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/1 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 similar to2-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.
引用
收藏
页码:901 / 909
页数:9
相关论文
共 39 条
[1]   Regulation of fatty acid oxidation by acetyl-CoA generated from glucose utilization in isolated myocytes [J].
Abdelaleem, S ;
Nada, MA ;
SayedAhmed, M ;
Hendrickson, SC ;
StLouis, J ;
Walthall, HP ;
Lowe, JE .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1996, 28 (05) :825-833
[2]   Human skeletal muscle carnitine palmitoyltransferase I activity determined in isolated intact mitochondria [J].
Berthon, PM ;
Howlett, RA ;
Heigenhauser, GJF ;
Spriet, LL .
JOURNAL OF APPLIED PHYSIOLOGY, 1998, 85 (01) :148-153
[3]   Lipoprotein secretion and triglyceride stores in the heart [J].
Björkegren, J ;
Véniant, M ;
Kim, SK ;
Withycombe, SK ;
Wood, PA ;
Hellerstein, MK ;
Neese, RA ;
Young, SG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (42) :38511-38517
[4]  
BLIGH EG, 1959, CAN J BIOCHEM PHYS, V37, P911
[5]   Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex [J].
Bowker-Kinley, MM ;
Davis, WI ;
Wu, PF ;
Harris, RA ;
Popov, KM .
BIOCHEMICAL JOURNAL, 1998, 329 :191-196
[6]   Differential expression of peroxisome proliferator-activated receptors (PPARs): Tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat [J].
Braissant, O ;
Foufelle, F ;
Scotto, C ;
Dauca, M ;
Wahli, W .
ENDOCRINOLOGY, 1996, 137 (01) :354-366
[7]   Identification of a subtype selective human PPARα agonist through parallel-array synthesis [J].
Brown, PJ ;
Stuart, LW ;
Hurley, KP ;
Lewis, MC ;
Winegar, DA ;
Wilson, JG ;
Wilkinson, WO ;
Ittoop, OR ;
Willson, TM .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (09) :1225-1227
[8]   Activators of peroxisome proliferator-activated receptor-α induce the expression of the uncoupling protein-3 gene in skeletal muscle -: A potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth [J].
Brun, S ;
Carmona, MC ;
Mampel, T ;
Viñas, O ;
Giralt, M ;
Iglesias, R ;
Villarroya, F .
DIABETES, 1999, 48 (06) :1217-1222
[9]   Physiological and nutritional regulation of enzymes of triacylglycerol synthesis [J].
Coleman, RA ;
Lewin, TM ;
Muoio, DM .
ANNUAL REVIEW OF NUTRITION, 2000, 20 :77-103
[10]   A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor α-deficient mice [J].
Djouadi, F ;
Weinheimer, CJ ;
Saffitz, JE ;
Pitchford, C ;
Bastin, J ;
Gonzalez, FJ ;
Kelly, DP .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 102 (06) :1083-1091