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Description

Peroxisome proliferator-activated receptor alpha (UniProt: Q07869, also known as PPAR-alpha, Nuclear receptor subfamily 1 group C member 1) is encoded by the PPARA (also known as NR1C1, PPAR) gene (Gene ID: 5465) in human. PPARs are members of the nuclear hormone receptor family of transcription factors that mediate a variety of cellular processes, including glucose and lipid metabolism, inflammatory responses, and regulation of apoptotic cell death. They act by binding to specific peroxisome proliferator-response elements (PPREs) on target genes. Three forms of PPARs have been described, which are designated as alpha, beta, and delta forms. PPAR alpha contains a DNA binding domain (aa 99-173) and a ligand-binding domain. It also has two NR C-4 type of zinc finger regions (aa 102-122 and 139-161) that bind to the regulator region of DNA when the receptor is activated. The ligand-binding domain has an extensive secondary structure of several alpha- helices and a beta-sheets. PPAR alpha heterodimerizes with RXRA and this heterodimerization is required for it DNA binding and transactivation activity. Two isoforms of PPAR alpha have been described that are produced by alternative splicing. PPAR alpha is expressed in skeletal muscle, liver, kidney, and endothelial cells and regulates lipoprotein metabolism. Its transcriptional activity is enhanced in the presence of insulin. Leukotriene B4 (LTB4) is shown to bind to PPAR alpha and induce transcription of genes of the omega and beta-oxidation pathways and clofibrate that binds to PPAR alpha accelerates catabolism of LTB4 in granulocytes and macrophages. PPARalpha-deficient mice show a prolonged inflammatory response when exposed to LTB4. GSK3-beta is reported to phosphorylate serine 73 on PPAR alpha, which in turn increases ubiquitination and protein turnover and reduces its activity.