scholarly journals Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα

2021 ◽  
Vol 22 (16) ◽  
pp. 8969
Author(s):  
Mounia Tahri-Joutey ◽  
Pierre Andreoletti ◽  
Sailesh Surapureddi ◽  
Boubker Nasser ◽  
Mustapha Cherkaoui-Malki ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Mammalian Cells ◽  
Atp Synthesis ◽  
Peroxisome Proliferator ◽  
Beta Oxidation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Pathway ◽  
Oxidative Phosphorylation Pathway ◽  
Peroxisome Proliferator Response Element ◽  
Peroxisomal Fatty Acid

In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal β-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid β-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid β-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients.

295. Peroxisome proliferator activated receptor-alpha is involved in H+-monocarboxylate transporter 2 and catalase protein expression in cultured preimplantation mouse embryos

2005 ◽  
Vol 17 (9) ◽  
pp. 125
Author(s):  
S. Jansen ◽  
M. Pantaleon ◽  
P. L. Kaye
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Mouse Embryos ◽  
Preimplantation Development ◽  
Monocarboxylate Transporter ◽  
Metabolic Inhibitors ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Beta Oxidation ◽  
Peroxisome Proliferator Activated Receptor

Cleavage stage embryos consume pyruvate before switching to glucose as the major energy substrate for blastocyst formation. This switch is conditional, because freshly collected two-cell embryos form blastocysts without glucose by increasing pyruvate consumption. Zygotes cultured without glucose cannot adapt in this way and degenerate, but paradoxically demonstrate upregulation of the H+-monocarboxylate transporter protein, MCT2, in morulae. MCT2 is a high affinity transporter implicated in redox shuttling for peroxisomal beta-oxidation of fatty acids.3 Fatty acids may provide energy for embryos2 but peroxisomal beta-oxidation has not been explored in preimplantation development. Rat oocytes possess a primitive peroxisomal system.1 The possibility therefore exists that MCT2 may also be linked to fatty acid metabolism in embryos. Peroxisome proliferator activated receptor (PPAR)-alpha is a transcriptional regulator of fatty acid transport and beta-oxidation, and controls expression of catalase, a major peroxisomal enzyme. This investigation explores the role of PPAR-α in the glucose-driven control of MCT2 expression in mouse embryos. Zygotes (18 h post-hCG) were cultured in KSOM in the presence or absence of glucose, or KSOM with selective agonists of PPAR-α, fenofibrate and WY 14643. Expression of MCT2 and catalase was analysed by confocal laser scanning immunohistochemistry and western blot. Results confirm the presence of catalase throughout preimplantation development. With glucose, cytoplasmic immunoreactivity for catalase was punctate and diffuse, while MCT2 was localised to apical membranes of outer blastomeres in morulae. Without glucose, catalase and MCT2 expression were increased with notable localisation of catalase to nuclei. This response was reflected in morulae cultured in the presence of glucose and PPAR-α agonists. These data suggest that PPAR-α plays a role in controlling catalase and MCT2 expression in embryos, and that conditions in the absence of glucose are more conducive for PPAR-α activation. (1)Figueroa C, Kawada ME, Veliz LP, Hidalgo U, Barros C, Gonzalez S and Santos MJ (2000) Peroxisomal proteins in rat gametes. Cell Biochem Biophys 32, 259–268.(2)Hewitson LC, Martin KL and Leese HJ (1996) Effects of metabolic inhibitors on mouse preimplantation embryo development and the energy metabolism of isolated inner cell masses. Mol Reprod Dev 43, 323–330.(3)McClelland GB, Khanna S, Gonzalez GF, Butz CE and Brooks GA (2003) Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system? Biochem Biophys Res Commun 304, 130–135.

scholarly journals Synthesis of DHA (omega-3 fatty acid): FADS2 gene polymorphisms and regulation by PPARα

OCL ◽  
2021 ◽  
Vol 28 ◽  
pp. 43
Author(s):  
Didier Majou
Keyword(s):  
Fatty Acid ◽  
Mapk Pathway ◽  
Promoter Polymorphism ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Omega 3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Omega 3 Fatty Acid ◽  
Peroxisome Proliferator Response Element ◽  
Δ6 Desaturase

In humans, in several biological systems, in particular the nervous system, the FADS2 gene transcribes Δ6-desaturase, which is the rate-limiting enzyme for converting α-linolenic acid into docosahexaenoic acid (an n-3 fatty acid). The peroxisome proliferator-activated receptor α (PPARα) modulates the transcription of FADS2 gene by interacting with a second transcription factor: the retinoid X receptor α (RXRα). These transcription factors take the form of a PPARα-RXRα heterodimer and are modulated by the ligands that modify their respective structures and enable them to bind to the peroxisome proliferator response element (PPRE) located in the promoter region of the FADS2 gene. Free estradiol induces the activation of PPARα via two pathways (i) transcription through genomic action mediated by an estrogen receptor; (ii) a non-genomic effect that allows for phosphorylation and activates PPARα via the ERK1/2-MAPK pathway. Phosphorylation is an on/off switch for PPARα transcription activity. Since Δ6-desaturase expression is retro-inhibited by free intracellular DHA in a dose-dependent manner, this position paper proposes an original hypothesis: if DHA simultaneously binds to both phosphorylated PPARα and RXRα, the resulting DHA-PPARαP-RXRα-DHA heterodimer represses FADS2 gene via PPRE. The retinoic acids-RARα-RXRα-DHA heterodimer would not dissociate from corepressors and would prevent coactivators from binding to FADS2. We speculate that SNPs, which are mostly located on PPRE, modulate the binding affinities of DHA-PPARαP-RXRα-DHA heterodimer to PPRE. The DHA-PPARαP-RXRα-DHA heterodimer’s greater affinity for PPRE results in a decreased production of D6D and DHA. FADS2 promoter polymorphism would increase the competition between DHA and other ligands, in accordance with their concentrations and affinities.

The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs

1993 ◽  
Vol 11 (1) ◽  
pp. 37-47 ◽  
Author(s):  
I Issemann ◽  
R A Prince ◽  
J D Tugwood ◽  
S Green
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Physiological Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisomal Enzyme ◽  
Oxidase Gene ◽  
Acyl Coa Oxidase ◽  
Peroxisome Proliferator Response Element

ABSTRACT The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about tenfold in the livers of treated rodents. We have previously shown that a peroxisome proliferator response element (PPRE) is located 570 bp upstream of the rat peroxisomal acyl CoA oxidase gene and that PPAR binds to it. We show here that the retinoid X receptor (RXR) is required for PPAR to bind to the PPRE, and that the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. We have also shown that a variety of hypolipidaemic drugs and fatty acids can activate PPAR. This supports the suggestion that the physiological role of PPAR is to regulate fatty acid homeostasis, and provides further evidence that PPAR is the target of the fibrate class of hypolipidaemic drugs. Finally, we have demonstrated that a metabolically stabilized fatty acid is a potent PPAR activator, suggesting that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR.

scholarly journals Differential Regulation of Peroxisome Proliferator-Activated Receptor (PPAR)-α1 and Truncated PPARα2 as an Adaptive Response to Fasting in the Control of Hepatic Peroxisomal Fatty Acid β-Oxidation in the Hibernating Mammal

Endocrinology ◽  
2008 ◽  
Vol 150 (3) ◽  
pp. 1192-1201 ◽  
Author(s):  
Zakaria El Kebbaj ◽  
Pierre Andreoletti ◽  
Driss Mountassif ◽  
Mostafa Kabine ◽  
Hervé Schohn ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Target Genes ◽  
Mitochondrial Pathway ◽  
Acid Oxidation ◽  
Splicing Regulation ◽  
Peroxisome Proliferator ◽  
Peroxisomal Membrane ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisomal Fatty Acid

Seasonal obesity and fasting-associated hibernation are the two major metabolic events governing hepatic lipid metabolism in hibernating mammals. In this process, however, the role of the nuclear receptor known as peroxisome proliferator-activated receptor (PPAR)-α has not been elucidated yet. Here we show, as in human, that jerboa (Jaculus orientalis) liver expresses both active wild-type PPARα (PPARα1wt) and truncated PPARα forms and that the PPARα1wt to truncated PPARα2 ratio, which indicates the availability of active PPARα1wt, is differentially regulated during fasting-associated hibernation. Functional activation of hepatic jerboa PPARα, during prehibernating and hibernating states, was demonstrated by the induction of its target genes, which encode peroxisomal proteins such as acyl-CoA oxidase 1, peroxisomal membrane protein 70, and catalase, accompanied by a concomitant induction of PPARα thermogenic coactivator PPARγ coactivator-1α. Interestingly, sustained activation of PPARα by its hypolipidemic ligand, ciprofibrate, abrogates the adaptive fasting response of PPARα during prehibernation and overinduces its target genes, disrupting the prehibernation fattening process. In striking contrast, during fasting-associated hibernation, jerboas exhibit preferential up-regulation of hepatic peroxisomal fatty acid oxidation instead of the mitochondrial pathway, which is down-regulated. Taken together, our results strongly suggest that PPARα is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which defines the activity of PPARα and the activation of its target genes during hibernation bouts of jerboas. Jerboa PPARα is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which define activation of PPARα and its target genes.

scholarly journals Activation of peroxisome proliferator-activated receptor-γ by rosiglitazone improves lipid homeostasis at the adipose tissue-liver axis in ethanol-fed mice

2012 ◽  
Vol 302 (5) ◽  
pp. G548-G557 ◽  
Author(s):  
Xiuhua Sun ◽  
Yunan Tang ◽  
Xiaobing Tan ◽  
Qiong Li ◽  
Wei Zhong ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Fatty Liver ◽  
Ethanol Exposure ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Peroxisomal Fatty Acid

The development of alcohol-induced fatty liver is associated with a reduction of white adipose tissue (WAT). Peroxisome proliferator-activated receptor (PPAR)-γ prominently distributes in the WAT and plays a crucial role in maintaining adiposity. The present study investigated the effects of PPAR-γ activation by rosiglitazone on lipid homeostasis at the adipose tissue-liver axis. Adult C57BL/6 male mice were pair fed liquid diet containing ethanol or isocaloric maltose dextrin for 8 wk with or without rosiglitazone supplementation to ethanol-fed mice for the last 3 wk. Ethanol exposure downregulated adipose PPAR-γ gene and reduced the WAT mass in association with induction of inflammation, which was attenuated by rosiglitazone. Ethanol exposure stimulated lipolysis but reduced fatty acid uptake capacity in association with dysregulation of lipid metabolism genes. Rosiglitazone normalized adipose gene expression and corrected ethanol-induced lipid dyshomeostasis. Ethanol exposure induced steatosis and upregulated inflammatory genes in the liver, which were attenuated by rosiglitazone. Hepatic peroxisomal fatty acid β-oxidation was suppressed by ethanol in associated with inhibition of acyl-coenzyme A oxidase 1. Rosiglitazone elevated plasma adiponectin level and normalized peroxisomal fatty acid β-oxidation rate. However, rosiglitazone did not affect ethanol-reduced very low-density lipoprotein secretion from the liver. These results demonstrated that activation of PPAR-γ by rosiglitazone reverses ethanol-induced adipose dysfunction and lipid dyshomeostasis at the WAT-liver axis, thereby abrogating alcoholic fatty liver.

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