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 language | English (US) |
|---|---|
| Pages (from-to) | 901-909 |
| Number of pages | 9 |
| Journal | Diabetes |
| Volume | 51 |
| Issue number | 4 |
| State | Published - 2002 |
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ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
Cite this
Peroxisome proliferator-activated receptor-α regulates fatty acid utilization in primary human skeletal muscle cells. / Muoio, Deborah M.; Way, James M.; Tanner, Charles J.; Winegar, Deborah A.; Kliewer, Steven A.; Houmard, Joseph A.; Kraus, William E.; Lynis Dohm, G.
In: Diabetes, Vol. 51, No. 4, 2002, p. 901-909.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Peroxisome proliferator-activated receptor-α regulates fatty acid utilization in primary human skeletal muscle cells
AU - Muoio, Deborah M.
AU - Way, James M.
AU - Tanner, Charles J.
AU - Winegar, Deborah A.
AU - Kliewer, Steven A.
AU - Houmard, Joseph A.
AU - Kraus, William E.
AU - Lynis Dohm, G.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0036224157&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036224157&partnerID=8YFLogxK
M3 - Article
C2 - 11916905
AN - SCOPUS:0036224157
VL - 51
SP - 901
EP - 909
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 4
ER -