PPARs: transcriptional effectors of fatty acids and their derivatives

Hihi, Abdelmadjid K.; Michalik, Liliane; Wahli, Walter

doi:10.1007/s00018-002-8467-x

Cited by 280 publications

(210 citation statements)

References 82 publications

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“…The observation that binding of non-fluorescent ligands significantly quenched the emission of PPARαΔAB aromatic amino acid residues (Figs. [1][2][3][4] suggests that ligand binding altered the conformation of PPARα. To further examine whether the binding of naturally-occurring VLCFA alter PPARα structure, the effect of these ligands on the circular dichroic (CD) spectra of PPARα was examined.…”

Section: Effect Of Very-long-chain Fatty Acids On Pparα Secondary Strmentioning

confidence: 99%

Very-Long-Chain and Branched-Chain Fatty Acyl-CoAs Are High Affinity Ligands for the Peroxisome Proliferator-Activated Receptor α (PPARα)

2006

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Very long chain fatty acids (VLCFA) and branched-chain fatty acids (BCFA) are potent inducers of the peroxisome proliferator-activated receptor PPARα, a nuclear receptor that enhances transcription of peroxisomal enzymes mediating β-oxidation of these potentially toxic fatty acids. However, it is not known whether the respective free fatty acids or their activated metabolites, i.e. CoA thioesters: (i) are the endogenous high-affinity PPARα ligands, (ii) alter PPARα conformation, and (iii) alter recruitment of coregulatory proteins to PPARα. As shown by quenching of PPARα intrinsic amino acid fluorescence, PPARα exhibited high affinity (3-29nM K d s) for the CoA thioesters of the common (C20-C24) VLCFA. In contrast, with the exception of arachidonic acid (K d =20nM), PPARα only weakly bound the VLCFA. PPARα also exhibited higher affinity for the CoA thioesters of BCFA (phytanoyl-CoA, pristanoyl-CoA; K d s near 11nM) than for the respective free branched-chain fatty acids. As shown by circular dichroism, the high affinity VLCFA-CoA and BCFA-CoA strongly altered PPARα conformation. Likewise, the high affinity VLCFA-CoA and BCFA-CoA altered cofactor recruitment to PPARα as shown by co-immunoprecipitation from liver homogenates. In contrast, nearly all the respective free fatty acids elicited only weak conformational changes in PPARα and did not alter co-factor recruitment to PPARα. In summary, the CoA thioesters of verylong-chain and branched-chain fatty acids are much more potent PPARα ligands than the free acids, resulting in altered PPARα conformation and cofactor recruitment. Since these are hallmarks of ligands-activated nuclear receptors, this suggests that the CoA thioesters are the active forms of these PPARα ligands.

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Section: Effect Of Very-long-chain Fatty Acids On Pparα Secondary Strmentioning

confidence: 99%

Very-Long-Chain and Branched-Chain Fatty Acyl-CoAs Are High Affinity Ligands for the Peroxisome Proliferator-Activated Receptor α (PPARα)

2006

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“…28 As concerns PPARg agonists, a range of fatty acids, including the polyunsaturated fatty acids, linoleic acid and arachidonic acid, was found to bind to PPARg and regulate gene transcription. 18,29,30 In a previous study we reported that the effects of CLA on cell growth or death in prostate and bladder cancer cells seemed to involve the PPARg isoform. 13 More recently, it has been suggested that the PPARsignaling pathway is connected with the b-catenin pathway.…”

mentioning

confidence: 94%

“…16,17 PPARs are ligand-activated transcription factors that are members of the nuclear hormone receptor superfamily. 18 As other ligand-activated transcriptional factors of this superfamily, PPARs heterodimerize with 9-cis retinoic acid receptors and interact with specific DNA response elements (PPRE) located upstream of the target genes. These include genes involved in lipid metabolism and in the regulation of cell cycle and differentiation.…”

mentioning

confidence: 99%

Involvement of PPARγ and E‐cadherin/β‐catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF‐7 cells

Bocca

Bozzo

Francica

et al. 2007

Intl Journal of Cancer

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Conjugated linoleic acid (CLA) is a naturally occurring fatty acid, which has been shown to exert beneficial effects against breast carcinogenesis. It has been reported that CLA could modulate cellular proliferation and differentiation through the activation of peroxisome proliferator-activated receptors (PPARs). Among different PPAR isotypes, PPARc is involved in growth inhibition of transformed cells. Ligands of PPARc are considered as potential anticancer drugs, so CLA was tested for its ability to induce PPARc expression in MCF-7 breast cancer cells. The effects of CLA and of a specific synthetic PPARc antagonist were evaluated on cell growth as well as on parameters responsible for cell growth regulation. We demonstrated here that CLA stimulated the expression of PPARc to levels up to control and caused PPARc translocation into the nucleus. Furthermore, the overexpression of PPARc positively correlates with the inhibition of cell proliferation and with the modulation of ERK signaling induced by CLA; in all cases the administration of the antagonist reverted CLA effects. The PPAR-signaling pathway is connected with the b-catenin/Ecadherin pathway, thus we evaluated CLA effects on the expression and cellular distribution of these proteins, which are involved in cell adhesion and responsible for invasive behavior. The treatment with CLA determined the up-regulation and the redistribution of b-catenin and E-cadherin and the antagonist reverted only the effect on b-catenin. These studies indicate that CLA regulates PPARc expression by selectively acting as an agonist and may influence cell-cell adhesion and invasiveness of MCF-7 cells. ' 2007 Wiley-Liss, Inc.

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“…The three PPAR isotypes (named ␣, ␤/␦, and ␥ or NR1C1, NR1C2, and NR1C3 (5)) are mainly involved in lipid and glucose homeostasis, regulation of food intake and body weight, and control of inflammation and wound healing (6,7). They are activated by naturally occurring or metabolized fatty acids derived from the diet or from intracellular signaling pathways and induce gene transcription as heterodimers with RXRs (8). PPARs are also very important therapeutic targets for the treatment of hyperlipidemia and type 2 diabetes.…”

mentioning

confidence: 99%

Fluorescence Imaging Reveals the Nuclear Behavior of Peroxisome Proliferator-activated Receptor/Retinoid X Receptor Heterodimers in the Absence and Presence of Ligand*♦

Feige

Gelman

Tudor

et al. 2005

Journal of Biological Chemistry

120

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In a global approach combining fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS), and fluorescence resonance energy transfer (FRET), we address the behavior in living cells of the peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors involved in lipid and glucose metabolism, inflammation control, and wound healing. We first demonstrate that unlike several other nuclear receptors, PPARs do not form speckles upon ligand activation. The subnuclear structures that may be observed under some experimental conditions result from overexpression of the protein and our immunolabeling experiments suggest that these structures are subjected to degradation by the proteasome. Interestingly and in contrast to a general assumption, PPARs readily heterodimerize with retinoid X receptor (RXR) in the absence of ligand in living cells. PPAR diffusion coefficients indicate that all the receptors are engaged in complexes of very high molecular masses and/or interact with relatively immobile nuclear components. PPARs are not immobilized by ligand binding. However, they exhibit a ligand-induced reduction of mobility, probably due to enhanced interactions with cofactors and/or chromatin. Our study draws attention to the limitations and pitfalls of fluorescent chimera imaging and demonstrates the usefulness of the combination of FCS, FRAP, and FRET to assess the behavior of nuclear receptors and their mode of action in living cells.

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PPARs: transcriptional effectors of fatty acids and their derivatives

Cited by 280 publications

References 82 publications

Very-Long-Chain and Branched-Chain Fatty Acyl-CoAs Are High Affinity Ligands for the Peroxisome Proliferator-Activated Receptor α (PPARα)

Very-Long-Chain and Branched-Chain Fatty Acyl-CoAs Are High Affinity Ligands for the Peroxisome Proliferator-Activated Receptor α (PPARα)

Involvement of PPARγ and E‐cadherin/β‐catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF‐7 cells

Fluorescence Imaging Reveals the Nuclear Behavior of Peroxisome Proliferator-activated Receptor/Retinoid X Receptor Heterodimers in the Absence and Presence of Ligand*♦

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