Properties of a fluorescent bezafibrate derivative (DNS‐X). A new tool to study peroxisome proliferation and fatty acid β‐oxidation

Berlot, Jean-Pierre; Lutz, Thomas; Malki, Mutaspha Cherkaoui; Nicolas-Francès, Valérie; Jannin, Brigitte; Latruffe, Norbert

doi:10.1007/s11745-000-0657-0

Cited by 3 publications

(2 citation statements)

References 23 publications

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“…It is also known that BEZA triggers the β-oxidation of fatty acids [34] and that acetate is needed for AF synthesis [5], [35] and, in relation to this, the enhancement of β-oxidation can fulfil this necessity; nevertheless, several papers have clearly shown that oxidative stress is a prerequisite for AF synthesis [12]–[14]. Being peroxisomes also a site for ROS and oxylipins generation [4], [36], [37], we sought the existence of a correlation among peroxisomal proliferation, the alteration of the cell redox balance, the formation of oxylipins and the biosynthesis of AF in A. flavus .…”

Section: Discussionmentioning

confidence: 99%

How Peroxisomes Affect Aflatoxin Biosynthesis in Aspergillus Flavus

et al. 2012

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In filamentous fungi, peroxisomes are crucial for the primary metabolism and play a pivotal role in the formation of some secondary metabolites. Further, peroxisomes are important site for fatty acids β-oxidation, the formation of reactive oxygen species and for their scavenging through a complex of antioxidant activities. Oxidative stress is involved in different metabolic events in all organisms and it occurs during oxidative processes within the cell, including peroxisomal β-oxidation of fatty acids. In Aspergillus flavus, an unbalance towards an hyper-oxidant status into the cell is a prerequisite for the onset of aflatoxin biosynthesis. In our preliminary results, the use of bezafibrate, inducer of both peroxisomal β-oxidation and peroxisome proliferation in mammals, significantly enhanced the expression of pex11 and foxA and stimulated aflatoxin synthesis in A. flavus. This suggests the existence of a correlation among peroxisome proliferation, fatty acids β-oxidation and aflatoxin biosynthesis. To investigate this correlation, A. flavus was transformed with a vector containing P33, a gene from Cymbidium ringspot virus able to induce peroxisome proliferation, under the control of the promoter of the Cu,Zn-sod gene of A. flavus. This transcriptional control closely relates the onset of the antioxidant response to ROS increase, with the proliferation of peroxisomes in A. flavus. The AfP33 transformant strain show an up-regulation of lipid metabolism and an higher content of both intracellular ROS and some oxylipins. The combined presence of a higher amount of substrates (fatty acids-derived), an hyper-oxidant cell environment and of hormone-like signals (oxylipins) enhances the synthesis of aflatoxins in the AfP33 strain. The results obtained demonstrated a close link between peroxisome metabolism and aflatoxin synthesis.

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Section: Discussionmentioning

confidence: 99%

How Peroxisomes Affect Aflatoxin Biosynthesis in Aspergillus Flavus

et al. 2012

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“…T o elucidate the interactions between ligands and PPARs or other peroxisome binding proteins, we developed a new probe, a fluorescent bezafibrate derivative, DNS-X [ 141. This molecule is able to trigger peroxisome proliferation both in oitro [14] and in oioo [15] and to undergo a PPARa activation by transfection assays. The PPAR-DNA response element is a direct repeat motif with a consensus sequence of TGACCT(T/A)TGACCT [16].…”

Section: Lipid Tmentioning

confidence: 99%

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

Latruffe

Cherkaoui-Malki

Nicolas-Francès

et al. 2001

Biochemical Society Transactions

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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.

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