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Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta.

Publication ,  Journal Article
Muoio, DM; MacLean, PS; Lang, DB; Li, S; Houmard, JA; Way, JM; Winegar, DA; Corton, JC; Dohm, GL; Kraus, WE
Published in: J Biol Chem
July 19, 2002

Ablation of peroxisome proliferator activated receptor (PPAR) alpha, a lipid-activated transcription factor that regulates expression of beta-oxidative genes, results in profound metabolic abnormalities in liver and heart. In the present study we used PPAR alpha knockout (KO) mice to determine whether this transcription factor is essential for regulating fuel metabolism in skeletal muscle. When animals were challenged with exhaustive exercise or starvation, KO mice exhibited lower serum levels of glucose, lactate, and ketones and higher nonesterified fatty acids than wild type (WT) littermates. During exercise, KO mice exhausted earlier than WT and exhibited greater rates of glycogen depletion in liver but not skeletal muscle. Fatty acid oxidative capacity was similar between muscles of WT and KO when animals were fed and only 28% lower in KO muscles when animals were starved. Exercise-induced regulation and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, two classical and robustly responsive PPAR alpha target genes, were similar between WT and KO in skeletal muscle but markedly different between genotypes in heart. Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPAR delta is severalfold more abundant than either PPAR alpha or PPAR gamma. In both human and rodent myocytes, the highly selective PPAR delta agonist GW742 increased fatty acid oxidation about 2-fold and induced expression of several lipid regulatory genes, including pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, responses that were similar to those elicited by the PPAR alpha agonist GW647. These results show redundancy in the functions of PPARs alpha and delta as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the delta-subtype can compensate for deficiency of PPAR alpha.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 19, 2002

Volume

277

Issue

29

Start / End Page

26089 / 26097

Location

United States

Related Subject Headings

  • Uncoupling Protein 3
  • Tyrosine
  • Transcription, Genetic
  • Transcription Factors
  • Thiazoles
  • Receptors, Cytoplasmic and Nuclear
  • Rats
  • Protein Kinases
  • Physical Conditioning, Animal
  • Oxidation-Reduction
 

Citation

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Muoio, D. M., MacLean, P. S., Lang, D. B., Li, S., Houmard, J. A., Way, J. M., … Kraus, W. E. (2002). Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. J Biol Chem, 277(29), 26089–26097. https://doi.org/10.1074/jbc.M203997200
Muoio, Deborah M., Paul S. MacLean, David B. Lang, Shi Li, Joseph A. Houmard, James M. Way, Deborah A. Winegar, J Christopher Corton, G Lynis Dohm, and William E. Kraus. “Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta.J Biol Chem 277, no. 29 (July 19, 2002): 26089–97. https://doi.org/10.1074/jbc.M203997200.
Muoio DM, MacLean PS, Lang DB, Li S, Houmard JA, Way JM, Winegar DA, Corton JC, Dohm GL, Kraus WE. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. J Biol Chem. 2002 Jul 19;277(29):26089–26097.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 19, 2002

Volume

277

Issue

29

Start / End Page

26089 / 26097

Location

United States

Related Subject Headings

  • Uncoupling Protein 3
  • Tyrosine
  • Transcription, Genetic
  • Transcription Factors
  • Thiazoles
  • Receptors, Cytoplasmic and Nuclear
  • Rats
  • Protein Kinases
  • Physical Conditioning, Animal
  • Oxidation-Reduction