Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone-bin ding proteins that regulate transcriptional responses to peroxisome prolife rators and structurally diverse fatty acids. PPARs have been implicated in a wide variety of functions, including lipid homeostasis and inflammatory r esponses. In this study, we examined the expression of PPAR-alpha in respon se to ambient hypoxia. Initial studies using microarray analysis of intesti nal epithelial mRNA revealed that hypoxia rapidly downregulates PPAR-alpha mRNA and protein in epithelial cells in vitro and in vivo. Subsequent studi es revealed that the PPAR-alpha gene bears a DNA consensus motif for the tr anscription factor hypoxia-inducible factor I (HIF-1). EMSA analysis reveal ed that ambient hypoxia induces HIF-1 alpha binding to the HIF-1 consensus domain of PPAR-alpha in parallel to HIF-1 nuclear accumulation, and antisen se depletion of HIF-1 alpha resulted in a loss of PPAR-alpha down-regulatio n. 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 tha t HIF-1-dependent down-regulation of PPAR-alpha may provide an adaptive res ponse to proinflammatory stimuli during cellular hypoxia. These studies pro vide unique insight into the regulation of PPAR-alpha expression and, impor tantly, provide an example of a down-regulatory pathway mediated by HIF-1.