Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia.
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone-binding proteins that regulate transcriptional responses to peroxisome proliferators and structurally diverse fatty acids. PPARs have been implicated in a wide variety of functions, including lipid homeostasis and inflammatory responses. In this study, we examined the expression of PPAR-alpha in response to ambient hypoxia. Initial studies using microarray analysis of intestinal epithelial mRNA revealed that hypoxia rapidly down-regulates PPAR-alpha mRNA and protein in epithelial cells in vitro and in vivo. Subsequent studies revealed that the PPAR-alpha gene bears a DNA consensus motif for the transcription factor hypoxia-inducible factor 1 (HIF-1). EMSA analysis revealed that ambient hypoxia induces HIF-1alpha binding to the HIF-1 consensus domain of PPAR-alpha in parallel to HIF-1 nuclear accumulation, and antisense depletion of HIF-1alpha resulted in a loss of PPAR-alpha down-regulation. The PPAR-alpha ligand pirinixic acid (WY14643) functionally promoted IFN-gamma-induced ICAM-1 expression in normoxic epithelia, and this response was lost in cells pre-exposed to ambient hypoxia. Such results indicate that HIF-1-dependent down-regulation of PPAR-alpha may provide an adaptive response to proinflammatory stimuli during cellular hypoxia. These studies provide unique insight into the regulation of PPAR-alpha expression and, importantly, provide an example of a down-regulatory pathway mediated by HIF-1.
Narravula
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Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Colgan
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D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000502:physiology*; D020675:Peroxisomes / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors