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

Abstract

The enzymes required for the β-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 density of peroxisomes in liver cells. These proliferators also induce simultaneously the expression of genes encoding acyl-CoA oxidase, enoyl-CoA hydratase-hydroxy-acyl-CoA dehydrogenase (multifunctional enzyme) and thiolase (3-ketoacyl-CoA thiolase). All these enzymes are responsible for long-chain and very-long-chain fatty acid β-oxidation in peroxisomes. Similar results were observed when rat hepatocytes, or liver-derived cell lines, were cultured 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-proliferatoractivated receptor α (PPARα). After activation by specific ligands, either fibrates or fatty acid derivatives, PPARα binds to a DNA response element: peroxisome-proliferator-responsive element (PPRE), which is a direct repeat of the following consensus sequence: TGACCTXTGACCT, found in the promoter region of the target genes. PPARα is expressed mainly in liver, intestine and kidney. PPARα is a transcriptional factor, which requires other nuclear proteins for function including retinoic acid X receptor (RXRα) and other regulatory proteins. From our results and others we suggest the role of PPARα in the regulation of the peroxisomal fatty acid β-oxidation. In this regard, we showed that although PPARα binds to thiolase B gene promoter at - 681 to - 669, a better response is observed with hepatic nuclear factor 4 (‘HNf-4’). Moreover, rat liver PPARα regulatory activity is dependent on its phosphorylated state. In contrast, a proteinkinase-C-mediated signal transduction pathway seems to be modified by peroxisome proliferators, leading to an increase in the phosphorylation level of specific proteins, some of which have been shown to be involved in the phosphoinositide metabolism.