A role for peroxisome proliferator-activated receptor alpha (PPAR alpha) in the control of cardiac malonyl-CoA levels

REDUCED FATTY ACID OXIDATION RATES AND INCREASED GLUCOSE OXIDATION RATES IN THE HEARTS OF MICE LACKING PPARa ARE ASSOCIATED WITH HIGHER CONCENTRATIONS OF MALONYL-CoA AND REDUCED EXPRESSION OF MALONYL-CoA DECARBOXYLASEREDUCED FATTY ACID OXIDATION RATES AND INCREASED GLUCOSE OXIDATION RATES IN THE HEARTS OF MICE LACKING PPARa ARE ASSOCIATED WITH HIGHER CONCENTRATIONS OF MALONYL-CoA AND REDUCED EXPRESSION OF MALONYL-CoA DECARBOXYLASE

Fiona Margaret Campbell, R Kozak, A Wagner, J Y Altarejos, J R B Dyck, D D Belke, D L Severson, D P Kelly, G D Lopaschuk

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    194 Citations (Scopus)

    Abstract

    Peroxisome proliferator-activated receptor alpha (PPAR)alpha is a nuclear receptor transcription factor that has an important role in controlling cardiac metabolic gene expression. We determined whether mice lacking PPARalpha (PPARalpha (-/-) mice) have alterations in cardiac energy metabolism. Rates of palmitate oxidation were significantly decreased in isolated working hearts from PPARalpha (-/-) hearts compared with hearts from age-matched wild type mice (PPARalpha (+/+) mice), (62 +/- 12 versus 154 +/- 65 nmol/g dry weight/min, respectively, p < 0.05). This was compensated for by significant increases in the rates of glucose oxidation and glycolysis. The decreased fatty acid oxidation in PPARalpha (-/-) hearts was associated with increased levels of cardiac malonyl-CoA compared with PPARalpha (+/+) hearts (15.15 +/- 1.63 versus 7.37 +/- 1.31 nmol/g, dry weight, respectively, p < 0.05). Since malonyl-CoA is an important regulator of cardiac fatty acid oxidation, we also determined if the enzymes that control malonyl-CoA levels in the heart are under transcriptional control of PPARalpha. Expression of both mRNA and protein as well as the activity of malonyl-CoA decarboxylase, which degrades malonyl-CoA, were significantly decreased in the PPARalpha (-/-) hearts. In contrast, the expression and activity of acetyl-CoA carboxylase, which synthesizes malonyl-CoA and 5'-AMP-activated protein kinase, which regulates acetyl-CoA carboxylase, were not altered. Glucose transporter expression (GLUT1 and GLUT4) was not different between PPARalpha (-/-) and PPARalpha (+/+) hearts, suggesting that the increase in glycolysis and glucose oxidation in the PPARalpha null mice was not due to direct effects on glucose uptake but rather was occurring secondary to the decrease in fatty acid oxidation. This study demonstrates that PPARalpha is an important regulator of fatty acid oxidation in the heart and that this regulation of fatty acid oxidation may in part occur due to the transcriptional control of malonyl-CoA decarboxylase.

    Original languageEnglish
    Pages (from-to)4098-4103
    Number of pages6
    JournalThe Journal of Biological Chemistry
    Volume277
    Issue number6
    DOIs
    Publication statusPublished - 8 Feb 2002

    Keywords

    • CARNITINE PALMITOYLTRANSFERASE-I
    • WORKING MOUSE HEART
    • LIPID-METABOLISM
    • GENE-EXPRESSION
    • PROTEIN-KINASE
    • DECARBOXYLASE
    • MUSCLE
    • TRANSCRIPTION
    • SUBSTRATE
    • CLONING

    Cite this

    @article{4585a293cff44ac58d4cc96e3c2e7918,
    title = "A role for peroxisome proliferator-activated receptor alpha (PPAR alpha) in the control of cardiac malonyl-CoA levels : REDUCED FATTY ACID OXIDATION RATES AND INCREASED GLUCOSE OXIDATION RATES IN THE HEARTS OF MICE LACKING PPARa ARE ASSOCIATED WITH HIGHER CONCENTRATIONS OF MALONYL-CoA AND REDUCED EXPRESSION OF MALONYL-CoA DECARBOXYLASEREDUCED FATTY ACID OXIDATION RATES AND INCREASED GLUCOSE OXIDATION RATES IN THE HEARTS OF MICE LACKING PPARa ARE ASSOCIATED WITH HIGHER CONCENTRATIONS OF MALONYL-CoA AND REDUCED EXPRESSION OF MALONYL-CoA DECARBOXYLASE",
    abstract = "Peroxisome proliferator-activated receptor alpha (PPAR)alpha is a nuclear receptor transcription factor that has an important role in controlling cardiac metabolic gene expression. We determined whether mice lacking PPARalpha (PPARalpha (-/-) mice) have alterations in cardiac energy metabolism. Rates of palmitate oxidation were significantly decreased in isolated working hearts from PPARalpha (-/-) hearts compared with hearts from age-matched wild type mice (PPARalpha (+/+) mice), (62 +/- 12 versus 154 +/- 65 nmol/g dry weight/min, respectively, p < 0.05). This was compensated for by significant increases in the rates of glucose oxidation and glycolysis. The decreased fatty acid oxidation in PPARalpha (-/-) hearts was associated with increased levels of cardiac malonyl-CoA compared with PPARalpha (+/+) hearts (15.15 +/- 1.63 versus 7.37 +/- 1.31 nmol/g, dry weight, respectively, p < 0.05). Since malonyl-CoA is an important regulator of cardiac fatty acid oxidation, we also determined if the enzymes that control malonyl-CoA levels in the heart are under transcriptional control of PPARalpha. Expression of both mRNA and protein as well as the activity of malonyl-CoA decarboxylase, which degrades malonyl-CoA, were significantly decreased in the PPARalpha (-/-) hearts. In contrast, the expression and activity of acetyl-CoA carboxylase, which synthesizes malonyl-CoA and 5'-AMP-activated protein kinase, which regulates acetyl-CoA carboxylase, were not altered. Glucose transporter expression (GLUT1 and GLUT4) was not different between PPARalpha (-/-) and PPARalpha (+/+) hearts, suggesting that the increase in glycolysis and glucose oxidation in the PPARalpha null mice was not due to direct effects on glucose uptake but rather was occurring secondary to the decrease in fatty acid oxidation. This study demonstrates that PPARalpha is an important regulator of fatty acid oxidation in the heart and that this regulation of fatty acid oxidation may in part occur due to the transcriptional control of malonyl-CoA decarboxylase.",
    keywords = "CARNITINE PALMITOYLTRANSFERASE-I, WORKING MOUSE HEART, LIPID-METABOLISM, GENE-EXPRESSION, PROTEIN-KINASE, DECARBOXYLASE, MUSCLE, TRANSCRIPTION, SUBSTRATE, CLONING",
    author = "Campbell, {Fiona Margaret} and R Kozak and A Wagner and Altarejos, {J Y} and Dyck, {J R B} and Belke, {D D} and Severson, {D L} and Kelly, {D P} and Lopaschuk, {G D}",
    year = "2002",
    month = "2",
    day = "8",
    doi = "10.1074/jbc.M106054200",
    language = "English",
    volume = "277",
    pages = "4098--4103",
    journal = "The Journal of Biological Chemistry",
    issn = "0021-9258",
    publisher = "AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC",
    number = "6",

    }

    TY - JOUR

    T1 - A role for peroxisome proliferator-activated receptor alpha (PPAR alpha) in the control of cardiac malonyl-CoA levels

    T2 - REDUCED FATTY ACID OXIDATION RATES AND INCREASED GLUCOSE OXIDATION RATES IN THE HEARTS OF MICE LACKING PPARa ARE ASSOCIATED WITH HIGHER CONCENTRATIONS OF MALONYL-CoA AND REDUCED EXPRESSION OF MALONYL-CoA DECARBOXYLASEREDUCED FATTY ACID OXIDATION RATES AND INCREASED GLUCOSE OXIDATION RATES IN THE HEARTS OF MICE LACKING PPARa ARE ASSOCIATED WITH HIGHER CONCENTRATIONS OF MALONYL-CoA AND REDUCED EXPRESSION OF MALONYL-CoA DECARBOXYLASE

    AU - Campbell, Fiona Margaret

    AU - Kozak, R

    AU - Wagner, A

    AU - Altarejos, J Y

    AU - Dyck, J R B

    AU - Belke, D D

    AU - Severson, D L

    AU - Kelly, D P

    AU - Lopaschuk, G D

    PY - 2002/2/8

    Y1 - 2002/2/8

    N2 - Peroxisome proliferator-activated receptor alpha (PPAR)alpha is a nuclear receptor transcription factor that has an important role in controlling cardiac metabolic gene expression. We determined whether mice lacking PPARalpha (PPARalpha (-/-) mice) have alterations in cardiac energy metabolism. Rates of palmitate oxidation were significantly decreased in isolated working hearts from PPARalpha (-/-) hearts compared with hearts from age-matched wild type mice (PPARalpha (+/+) mice), (62 +/- 12 versus 154 +/- 65 nmol/g dry weight/min, respectively, p < 0.05). This was compensated for by significant increases in the rates of glucose oxidation and glycolysis. The decreased fatty acid oxidation in PPARalpha (-/-) hearts was associated with increased levels of cardiac malonyl-CoA compared with PPARalpha (+/+) hearts (15.15 +/- 1.63 versus 7.37 +/- 1.31 nmol/g, dry weight, respectively, p < 0.05). Since malonyl-CoA is an important regulator of cardiac fatty acid oxidation, we also determined if the enzymes that control malonyl-CoA levels in the heart are under transcriptional control of PPARalpha. Expression of both mRNA and protein as well as the activity of malonyl-CoA decarboxylase, which degrades malonyl-CoA, were significantly decreased in the PPARalpha (-/-) hearts. In contrast, the expression and activity of acetyl-CoA carboxylase, which synthesizes malonyl-CoA and 5'-AMP-activated protein kinase, which regulates acetyl-CoA carboxylase, were not altered. Glucose transporter expression (GLUT1 and GLUT4) was not different between PPARalpha (-/-) and PPARalpha (+/+) hearts, suggesting that the increase in glycolysis and glucose oxidation in the PPARalpha null mice was not due to direct effects on glucose uptake but rather was occurring secondary to the decrease in fatty acid oxidation. This study demonstrates that PPARalpha is an important regulator of fatty acid oxidation in the heart and that this regulation of fatty acid oxidation may in part occur due to the transcriptional control of malonyl-CoA decarboxylase.

    AB - Peroxisome proliferator-activated receptor alpha (PPAR)alpha is a nuclear receptor transcription factor that has an important role in controlling cardiac metabolic gene expression. We determined whether mice lacking PPARalpha (PPARalpha (-/-) mice) have alterations in cardiac energy metabolism. Rates of palmitate oxidation were significantly decreased in isolated working hearts from PPARalpha (-/-) hearts compared with hearts from age-matched wild type mice (PPARalpha (+/+) mice), (62 +/- 12 versus 154 +/- 65 nmol/g dry weight/min, respectively, p < 0.05). This was compensated for by significant increases in the rates of glucose oxidation and glycolysis. The decreased fatty acid oxidation in PPARalpha (-/-) hearts was associated with increased levels of cardiac malonyl-CoA compared with PPARalpha (+/+) hearts (15.15 +/- 1.63 versus 7.37 +/- 1.31 nmol/g, dry weight, respectively, p < 0.05). Since malonyl-CoA is an important regulator of cardiac fatty acid oxidation, we also determined if the enzymes that control malonyl-CoA levels in the heart are under transcriptional control of PPARalpha. Expression of both mRNA and protein as well as the activity of malonyl-CoA decarboxylase, which degrades malonyl-CoA, were significantly decreased in the PPARalpha (-/-) hearts. In contrast, the expression and activity of acetyl-CoA carboxylase, which synthesizes malonyl-CoA and 5'-AMP-activated protein kinase, which regulates acetyl-CoA carboxylase, were not altered. Glucose transporter expression (GLUT1 and GLUT4) was not different between PPARalpha (-/-) and PPARalpha (+/+) hearts, suggesting that the increase in glycolysis and glucose oxidation in the PPARalpha null mice was not due to direct effects on glucose uptake but rather was occurring secondary to the decrease in fatty acid oxidation. This study demonstrates that PPARalpha is an important regulator of fatty acid oxidation in the heart and that this regulation of fatty acid oxidation may in part occur due to the transcriptional control of malonyl-CoA decarboxylase.

    KW - CARNITINE PALMITOYLTRANSFERASE-I

    KW - WORKING MOUSE HEART

    KW - LIPID-METABOLISM

    KW - GENE-EXPRESSION

    KW - PROTEIN-KINASE

    KW - DECARBOXYLASE

    KW - MUSCLE

    KW - TRANSCRIPTION

    KW - SUBSTRATE

    KW - CLONING

    U2 - 10.1074/jbc.M106054200

    DO - 10.1074/jbc.M106054200

    M3 - Article

    VL - 277

    SP - 4098

    EP - 4103

    JO - The Journal of Biological Chemistry

    JF - The Journal of Biological Chemistry

    SN - 0021-9258

    IS - 6

    ER -