Peroxisome proliferator-activated receptors: insight into multiple cellular functions

Escher, Pascal; Wahli, Walter

doi:10.1016/s0027-5107(99)00231-6

Cited by 431 publications

(308 citation statements)

References 152 publications

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“…7, B and D) was compared with that of HNF-4␣-E-F (aa 132-455) described previously (19). cis-Parinaric acid quenched the full-length HNF-4␣, HNF-4␣-E-F (aa 132-455), and HNF-4␣-E (aa 132-370) by 49,59, and 55%, respectively, when Tyr and Trp residues were excited at 280 nm. A closer distribution of quenching percentages for cis-parinaric acid when compared with cis-parinaroyl-CoA, suggested that the free fatty acid interacted mostly with Tyr residues present in the E-domain, whereas the fatty acyl-CoA interacted with Tyr residues in both the E-and F-domains.…”

Section: Intrinsic Fluorescence Characteristics Of Full-length Hnf-4␣mentioning

confidence: 89%

Role of Regulatory F-domain in Hepatocyte Nuclear Factor-4α Ligand Specificity

Petrescu¹,

Hertz

Bar‐Tana

et al. 2005

Journal of Biological Chemistry

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Section: Intrinsic Fluorescence Characteristics Of Full-length Hnf-4␣mentioning

confidence: 89%

Role of Regulatory F-domain in Hepatocyte Nuclear Factor-4α Ligand Specificity

Petrescu¹,

Hertz

Bar‐Tana

et al. 2005

Journal of Biological Chemistry

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“…Wy-14,643, a PPARα activator, increased transcription of the human Δ6 desaturase gene by 500%, an effect that was dependent upon PPARα expression [41]. Most interestingly, the natural endogenous activators of PPARs include specific unsaturated fatty acids and eicosanoid-like fatty acid derivatives [42]. Factors that affect desaturase gene expression via SREBP1c include insulin and oxysterols (via LXR) that stimulate, and HUFA, glucagon, adrenalin and steroid hormones that inhibit.…”

Section: Discussionmentioning

confidence: 99%

Environmental and dietary influences on highly unsaturated fatty acid biosynthesis and expression of fatty acyl desaturase and elongase genes in liver of Atlantic salmon (Salmo salar)

Zheng

Torstensen²,

Tocher

et al. 2005

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

184

160

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Highly unsaturated fatty acid (HUFA) synthesis in Atlantic salmon (Salmo salar) was known to be influenced by both nutritional and environmental factors. Here we aimed to test the hypothesis that both these effectors involved similar molecular mechanisms. Thus, HUFA biosynthetic activity and the expression of fatty acyl desaturase and elongase genes were determined at various points during an entire two year production cycle in salmon fed diets containing either 100% fish oil or diets in which a high proportion (75% and 100%) of fish oil was replaced by C 18 polyunsaturated fatty acid-rich vegetable oil. The results showed that HUFA biosynthesis in Atlantic salmon varied during the growth cycle with peak activity around seawater transfer and subsequent low activities in seawater. Consistent with this, gene expression of Δ6 desaturase, the rate-limiting step in the HUFA biosynthetic pathway, was highest around the point of seawater transfer and lowest during the seawater phase. In addition, the expression of both Δ6 and Δ5 desaturase genes was generally higher in fish fed the vegetable oilsubstituted diets compared to fish fed fish oil, particularly in the seawater phase. Again, generally consistent with this, the activity of the HUFA biosynthetic pathway was invariably higher in fish fed diets in which fish oil was substituted by vegetable oil compared to fish fed only fish oil. In conclusion, these studies showed that both nutritional and environmental modulation of HUFA biosynthesis in Atlantic salmon involved regulation of fatty acid desaturase gene expression.3

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“…In summary, while many of the above experiments are suggestive that the CoA thioesters of VLCFA and BCFA represent functional ligands for PPARα, it remains to be shown whether the VLCFA, BCFA, or their CoA thioesters exhibit characteristic hallmarks of endogenous ligands that bind to PPARα: (i) high (K d s in nM range) affinity, (ii) physically alter the structure/conformation of the PPARα protein, and (iii) affect co-factor recruitment PPARα (26). The objective of the present study was to begin to resolve these issues through use of direct ligand binding assays (i.e.…”

mentioning

confidence: 98%

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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Peroxisome proliferator-activated receptors: insight into multiple cellular functions

Cited by 431 publications

References 152 publications

Role of Regulatory F-domain in Hepatocyte Nuclear Factor-4α Ligand Specificity

Role of Regulatory F-domain in Hepatocyte Nuclear Factor-4α Ligand Specificity

Environmental and dietary influences on highly unsaturated fatty acid biosynthesis and expression of fatty acyl desaturase and elongase genes in liver of Atlantic salmon (Salmo salar)

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

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