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

Laboratoire de Biologie Moléculaire et Cellulaire (LBMC), University of Burgundy, 6 boulevard Gabriel, 21000 Dijon, France.
Biochemical Society Transactions (Impact Factor: 3.19). 06/2001; 29(Pt 2):305-9. DOI: 10.1042/BST0290305
Source: PubMed


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 density of peroxisomes in liver cells. These proliferators also induce simultaneously the expression of genes encoding acyl-CoA oxidase, enoyl-CoA hydratase-hydroxyacyl-CoA dehydrogenase (multifunctional enzyme) and thiolase (3-ketoacyl-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 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-proliferator-activated receptor alpha (PPARalpha). After activation by specific ligands, either fibrates or fatty acid derivatives, PPARalpha 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. PPARalpha is expressed mainly in liver, intestine and kidney. PPARalpha is a transcriptional factor, which requires other nuclear proteins for function including retinoic acid X receptor (RXRalpha) and other regulatory proteins. From our results and others we suggest the role of PPARalpha in the regulation of the peroxisomal fatty acid beta-oxidation. In this regard, we showed that although PPARalpha 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 PPARalpha regulatory activity is dependent on its phosphorylated state. In contrast, a protein-kinase-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.

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    • "In the nucleus, PPARs form heterodimers with retinoic acid receptors (RXR) [10-12]. The generally conserved domain structures are found in PPARs and RXRs: DNA-binding domains, ligand-binding domains, and activation domains. "
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    • "Since both THL and AOX genes are well known PPARtarget genes [44], the decrease of these proteins may be interpreted as a consequence of the decrease of this transcription factor. In fact, PPAR appears downregulated in our experimental conditions, after both acute and 14-DIV chronic treatment. "
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    • "In mammals, PPARα is a nuclear receptor controlling peroxisome proliferation and lipid catabolism whereas PPARγ participates in lipid accumulation (Escher and Wahli, 2000). AOX1 is the first and rate-limiting enzyme of the peroxisomal β-oxidation pathway whose transcription is regulated via PPARs (Lattruffe et al., 2001; Mandard et al., 2004). RXR on its side is the obligate heterodimerization partner of PPARs (Mangelsdorf and Evans, 1995) and is a key regulator of metabolism (Desvergne , 2007). "
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