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
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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ABSTRACT: Although glucose-lowering treatment shows some risk lowering effects in cardiovascular diseases, risks of macrovascular and microvascular complications have still remained, and development of new therapeutic strategies is needed. Recent data have shown that peroxisome proliferator activated receptor-α (PPAR-α) plays a pivotal role in the regulation of lipid homeostasis, fatty acid oxidation, cellular differentiation, and immune response such as inflammation or vascularization related to diabetic complication. This review will re-examine the metabolic role of PPAR-α, summarize data from clinical studies on the effect of PPAR-α agonist in diabetes, and will discuss the possible therapeutic role of PPAR-α activation.
Available from: Loredana Cristiano
- "Since both THL and AOX genes are well known PPARtarget genes , 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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ABSTRACT: The central role of peroxisomes in reactive oxygen species and lipid metabolism and their importance in brain functioning are well established. The aim of this work has been to study the peroxisomal population in the Tg2576 mouse model of Alzheimer's disease (AD), at the age of three months when no apparent signs of behavioral, neuroanatomical, cytological, or biochemical alterations have been so far described. The expression and localization of peroxisomal (PMP70, CAT, AOX, and THL) and peroxisome-related proteins (PEX5p, GPX1, SOD1, and SOD2) were studied in the neocortex and hippocampus of transgenic and wild-type animals. Oxidative stress markers (TBARS, acrolein, and 8-OHG) were also evaluated. Our results demonstrate that significant alterations are already detectable at this early stage of the disease and also involve peroxisomes. Their number and protein composition change concomitantly with early oxidative stress. Interestingly, the neocortex shows a compensatory response, consisting in an increase of reactive oxygen species scavenging enzymes, while the hippocampus appears more prone to the oxidative insult. This different behavior could be related to metabolic differences in the two brain areas, also involving peroxisome abundance and/or enzymatic content.
Available from: Oihane Diaz de Cerio
- "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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ABSTRACT: In November 2002 the tanker Prestige released more than 60,000t of a heavy fuel oil which spread over Galician waters and the Biscay Bay, affecting coastal ecosystems. Polycyclic aromatic hydrocarbons are the main components of the Prestige fuel oil and induce biotransformation metabolism and peroxisome proliferation in marine organisms. In vertebrates, this later response involves peroxisome proliferator-activated receptors (PPARs), transcription factors belonging to the nuclear receptor superfamily, that act upon heterodimerization with the retinoid X receptor (RXR). In order to assess the possible biological effects of the Prestige oil spill in the Biscay Bay, male and female juvenile and adult European hakes Merluccius merluccius were sampled in June and December 2004 and 2005. PCR screening of hake liver cDNA with degenerate primers resulted in cloning and sequencing of cDNA fragments of PPARα (1011bp), PPARγ (812bp), RXR (270bp) and of the PPARα target gene palmitoyl-CoA oxidase (AOX1, 792bp). Fragments of another 9 toxicologically relevant genes were also cloned and sequenced. PPARα mRNA expression was not significantly different among groups. In juvenile females transcription of PPARγ, RXR and AOX1 significantly increased in June 2005 when compared to June 2004. In adult males levels of AOX1 decreased in the same period. AOX1 and 7-ethoxyresorufin O-deethylase (EROD) activities, measured as exposure biomarkers, differed between years only in males sampled in June. EROD activity was higher in 2004 than in 2005 in adults, whereas both juvenile and adults showed higher AOX1 activity in 2005. The lack of historical data previous to the accident or in areas not affected by the accident did not allow to relate observed variations in gene transcription levels and enzyme activities to the Prestige oil spill. Reported data could be useful for comparison purposes for future studies in European hake and contributes gene sequence information relevant for future toxicological studies.
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