Hypoxia-inducible factor 1 mediates hypoxia-induced cardiomyocyte lipid accumulation by reducing the DNA binding activity of peroxisome proliferator-activated receptor alpha/retinoid X receptor.
In response to cellular hypoxia, cardiomyocytes adapt to consume less oxygen by shifting ATP production from mitochondrial fatty acid beta-oxidation to glycolysis. The transcriptional activation of glucose transporters and glycolytic enzymes by hypoxia is mediated by hypoxia-inducible factor 1 (HIF-1). In this study, we examined whether HIF-1 was involved in the suppression of mitochondrial fatty acid beta-oxidation in hypoxic cardiomyocytes. We showed that either hypoxia or adenovirus-mediated expression of a constitutively stable hybrid form (HIF-1alpha/VP16) suppressed mitochondrial fatty acid metabolism, as indicated by an accumulation of intracellular neutral lipid. Both treatments also reduced the mRNA levels of muscle carnitine palmitoyltransferase I which catalyzes the rate-limiting step in the mitochondrial import of fatty acids for beta-oxidation. Furthermore, adenovirus-mediated expression of HIF-1alpha/VP16 in cardiomyocytes under normoxic conditions also mimicked the reduction in the DNA binding activity of peroxisome proliferator-activated receptor alpha (PPARalpha)/retinoid X receptor (RXR), in the presence or absence of a PPARalpha ligand. These results suggest that HIF-1 may be involved in hypoxia-induced suppression of fatty acid metabolism in cardiomyocytes by reducing the DNA binding activity of PPARalpha/RXR.
Belanger
Adam J
AJ
Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701, USA.
Luo
Zhengyu
Z
Vincent
Karen A
KA
Akita
Geoffrey Y
GY
Cheng
Seng H
SH
Gregory
Richard J
RJ
Jiang
Canwen
C
D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D051381:Rats; D047488:Retinoid X Receptors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D047493:PPAR alpha; D047488:Retinoid X Receptors; D004247:DNA