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

• Published in: Biochemical and biophysical research communications Vol. 364; no. 3
• Main Authors: Belanger, Adam J., Luo Zhengyu, Vincent, Karen A., Akita, Geoffrey Y., Cheng, Seng H., Gregory, Richard J., Jiang Canwen
• Format: Journal Article
• Language: English
• Published: United States 21.12.2007
• Subjects: 60 APPLIED LIFE SCIENCES; ADENOVIRUS; ANOXIA; ATP; CARNITINE; DNA; ENZYMES; GLUCOSE; GLYCOLYSIS; HYBRIDIZATION; LIGANDS; LIPIDS; MITOCHONDRIA; MUSCLES; OXIDATION; RECEPTORS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.10.062

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-1{alpha}/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-1{alpha}/VP16 in cardiomyocytes under normoxic conditions also mimicked the reduction in the DNA binding activity of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha})/retinoid X receptor (RXR), in the presence or absence of a PPAR{alpha} 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 PPAR{alpha}/RXR.