Fatty Acids, Eicosanoids, and Hypolipidemic Agents Identified as Ligands of Peroxisome Proliferator-Activated Receptors by Coactivator-Dependent Receptor Ligand Assay

Krey, Grigorios

doi:10.1210/me.11.6.779

Cited by 629 publications

(596 citation statements)

References 0 publications

Supporting

Mentioning

551

Contrasting

Unclassified

Order By: Relevance

“…For example, early transactivation assays show: (i) PPARα is activated by polyunsaturated VLCFA (C20:4, C20:5, C22:6), but not monounsaturated VLCFA (C24:1, C22:1) (3), (ii) n-3 polyunsaturated VLCFA elicited similar PPARα activation levels as n-6 polyunsaturated VLCFA (3). These findings of VLCFA being potential PPARα ligands were supported by gelshift assays (14) and co-activator-dependent receptor ligand assays (15). Likewise, transactivation studies with branched-chain fatty acids also show PPARα activation by BCFA (11).…”

Section: Discussionmentioning

confidence: 83%

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

2006

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 83%

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

2006

View full text Add to dashboard Cite

show abstract

“…PPAR-a is generally regarded as a metabolic sensor of diet-derived fatty acids [44,45]. According to this view, PPAR-a may be activated by the heightened levels of non-esterified fatty acids reached in tissues after a meal.…”

Section: The Fatty-acid Sensor Hypothesis Revisitedmentioning

confidence: 99%

Regulation of food intake by oleoylethanolamide

Verme

Gaetani

et al. 2005

CMLS, Cell. Mol. Life Sci.

157

130

View full text Add to dashboard Cite

Abstract. Oleoylethanolamide (OEA), the naturally occurring amide of ethanolamine and oleic acid, is an endogenous lipid that modulates feeding, body weight and lipid metabolism by binding with high affinity to the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-a). In the CMLS, Cell. Mol. Life Sci. 62 (2005) 708 -716 1420-682X/05/060708-09 DOI 10.1007/s00018-004-4494-0 © Birkhäuser Verlag, Basel, 2005 CMLS Cellular and Molecular Life Sciencespresent article, we describe the biochemical pathways responsible for the initiation and termination of OEA signaling, and outline the pharmacological properties of this compound in relation to its ability to activate PPARa. Finally, we discuss the possible role of OEA as a peripheral satiety hormone.

show abstract

“…This includes both saturated and unsaturated fatty acids, though in general PUFA are more potent. All three PPAR subtypes have been shown to bind both n-3 and n-6 PUFA (Krey et al, 1997;Kliewer et al, 1997). In general, PUFA bind best to PPARa followed by PPARg and PPARb (Krey et al, 1997).…”

Section: Nuclear Receptorsmentioning

confidence: 99%

“…All three PPAR subtypes have been shown to bind both n-3 and n-6 PUFA (Krey et al, 1997;Kliewer et al, 1997). In general, PUFA bind best to PPARa followed by PPARg and PPARb (Krey et al, 1997). Furthermore, a range of eicosanoids, derived form n-3 and n-6 PUFA, have also When this dimer is bound in the absence of ligand, they may interact with co-repressors and gene transcription will be inhibited.…”

Section: Nuclear Receptorsmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of gene transcription by fatty acids

Salter

Tarling

2007

Animal

View full text Add to dashboard Cite

Dietary fat is well recognised as an important macronutrient that has major effects on growth, development and health of all animals including humans. The amount and type of fat in the diet impacts on many aspects of metabolism including lipoprotein pathways, lipid synthesis and oxidation, adipocyte differentiation and cholesterol metabolism. It has become increasingly apparent that many of these effects may be due to direct modulation of expression of key genes through the interaction of fatty acids with certain transcription factors. Peroxisome proliferator-activated receptors (PPARs), the liver X receptors (LXRs), hepatic nuclear factor 4 (HNF-4) and sterol regulatory binding proteins (SREBPs) represent four such factors. This review focuses on emerging evidence that the activity of these transcription factors are regulated by fatty acids and the interactions between them may be responsible for many of the effects of fatty acids on metabolism and the development of chronic disease.

show abstract

Fatty Acids, Eicosanoids, and Hypolipidemic Agents Identified as Ligands of Peroxisome Proliferator-Activated Receptors by Coactivator-Dependent Receptor Ligand Assay

Cited by 629 publications

References 0 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)

Regulation of food intake by oleoylethanolamide

Regulation of gene transcription by fatty acids

Contact Info

Product

Resources

About