These genetic disorders arise from defects in enzymes of the peroxisomal β-oxidation pathway which result in accumulation of VLCFA, BCFA, and their thioesters ( 6- 8).
VLCFA and BCFA accumulation are associated with human neurological disorders including Zellweger syndrome, X-linked adrenoleukodystrophy, Refsum disease, and MFP-2 deficiency ( 6- 8). PPRE exist within many of the genes involved in fatty acid oxidation and cell differentiation, suggesting that PPAR are responsible for regulating transcription of these genes ( 5).Īn especially important role of PPARα is inducing transcription of multiple peroxisomal enzymes required for β-oxidation of very-long-chain fatty acids (VLCFA) and branched-chain fatty acids (BCFA). Ligand binding to one and, even more so, both receptors greatly potentiates transcription (rev. Independent of ligand binding, a basal level of transcription occurs by PPAR forming a heterodimer with the retinoid X receptor (RXR) which binds to a specific DNA response element (PPRE) within the target genes ( 3, 4). Although there is some overlap in ligand specificity, unique isotype binding occurs by a variety of xenobiotics depends upon specific amino acid substitutions within the PPAR ligand-binding pocket ( 1, 2). Each isotype, encoded by a different gene, is differentially expressed in select tissues and expression levels depend on cellular processes (rev. PPAR have been identified in several species, with at least three isotypes recognized (α, β/δ, γ). Peroxisome proliferator-activated receptors (PPAR) are ligand-activated members of the steroid/thyroid nuclear hormone receptor superfamily. 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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In summary, the CoA thioesters of very-long-chain and branched-chain fatty acids are much more potent PPARα ligands than the free acids, resulting in altered PPARα conformation and cofactor recruitment.
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. Likewise, the high affinity VLCFA-CoA and BCFA-CoA altered co-factor recruitment to PPARα as shown by co-immunoprecipitation from liver homogenates. As shown by circular dichroism, the high affinity VLCFA-CoA and BCFA-CoA strongly altered PPARα conformation. PPARα also exhibited higher affinity for the CoA thioesters of BCFA (phytanoyl-CoA, pristanoyl-CoA K ds near 11nM) than for the respective free branched-chain fatty acids. In contrast, with the exception of arachidonic acid (K d=20nM), PPARα only weakly bound the VLCFA. As shown by quenching of PPARα intrinsic amino acid fluorescence, PPARα exhibited high affinity (3-29nM K ds) for the CoA thioesters of the common (C20-C24) VLCFA. CoA thioesters: (i) are the endogenous high-affinity PPARα ligands, (ii) alter PPARα conformation, and (iii) alter recruitment of coregulatory proteins to PPARα. However, it is not known whether the respective free fatty acids or their activated metabolites, i.e. 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.
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