Peroxisome-proliferator-activated receptors as physiological sensors of fatty acid metabolism: molecular regulation in peroxisomes

The enzymes required for the beta -oxidation of fatty acyl-CoA are present in peroxisomes and mitochondria. Administration of hypolipidaemic compounds such as clofibrate to rodents leads to an increase in the volume and densi ty of peroxisomes in liver cells, These proliferators also induce simultane ously the expression of genes encoding acyl CoA oxidase, enoyl-CoA hydratas e-hydroxyacyl-CoA dehydrogenase (multifunctional enzyme) and thiolase (3-ke toacyl-CoA thiolase). All these enzymes are responsible for long-chain and very-long-chain fatty acid beta -oxidation in peroxisomes, Similar results were observed when rat hepatocytes, or liver-derived cell lines, were cultu red with a peroxisome proliferator. The increased expression of these genes is due to the stimulation of their transcription rate. These results show that the peroxisome proliferators act on the hepatic cells and regulate the transcription through various cellular components and pathways, including peroxisome-proliferator-activated receptor alpha (PPAR alpha), After activa tion by specific ligands, either fibrates or fatty acid derivatives, PPAR a lpha binds to a DNA response element: peroxisome-proliferator-responsive el ement (PPRE), which is a direct repeat of the following consensus sequence: TGACCTXTCACCT, found in the promoter region of the target genes. PPAR alph a is expressed mainly in liver, intestine and kidney. PPAR alpha is a trans criptional factor, which requires other nuclear proteins for function inclu ding retinoic acid X receptor (RXR alpha) and other regulatory proteins. Fr om our results and others we suggest the role of PPAR alpha in the regulati on of the peroxisomal fatty acid beta -oxidation. In this regard, we showed that although PPAR alpha binds to thiolase B gene promoter at -681 to -669 , a better response is observed with hepatic nuclear factor 4 ('HNf-4'). Mo reover, rat liver PPAR alpha regulatory activity is dependent on its phosph orylated state. In contrast, a protein-kinase-C-mediated signal transductio n pathway seems to be modified by peroxisome proliferators, leading to an i ncrease in the phosphorylation level of specific proteins, some of which ha ve been shown to be involved in the phosphoinositide metabolism.