Molecular Recognition of Fatty Acids by Peroxisome Proliferator–Activated Receptors

Xu, H. Eric; Lambert, Millard H.; Montana, V.G.; Parks, Derek J.; Blanchard, Steven G.; Brown, Peter J.; Sternbach, Daniel D.; Lehmann, Jürgen; Wisely, G. Bruce; Willson, Timothy M.; Kliewer, Steven A.; Milburn, Michael V.

doi:10.1016/s1097-2765(00)80467-0

Cited by 1,033 publications

(798 citation statements)

References 28 publications

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“…However, the interaction between the PPAR-delta À87T4C and the P:S ratio on features on the MS did not reach statistical significance (not shown). Furthermore, we cannot exclude the possibility of an interaction with other PPAR isoforms as fatty acids are ligands for all three PPARs, 13,31 all PPARs exert their effect via shared metabolic pathways including lipid transport and metabolism. PPAR-delta is also expressed in tissues where PPARa and PPARg are expressed.…”

Section: Discussionmentioning

confidence: 99%

Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta −87T>C polymorphism and dietary fat in French-Canadians

et al. 2006

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The metabolic syndrome (MS) is influenced by genetic and environmental factors. Peroxisome proliferator-activated receptor delta (PPAR-delta), a transcription factor involved in lipid metabolism, is a candidate gene for the MS. Objective: We verified whether genetic variants in this gene are associated with the MS and whether dietary fatty acids interact with the À87T4C polymorphism. Methods: By direct sequencing, we identified 15 variants in the PPAR-delta gene and analyses were pursued with the À87T4C polymorphism for 340 subjects. Results: Metabolic variables were comparable among each genotype group. The À87T4C polymorphism, fat intake and the interaction accounted, respectively for 2.2, 1.9 and 1.5% of the variance in high-density lipoprotein cholesterol (HDL-C) levels (Po0.05) (age, sex and energy intake were included into the model). The total cholesterol/HDL-C ratio was also modulated by a gene-diet interaction and by the -87T4C polymorphism (Po0.05). No gene-diet interaction effects were observed for other features of the MS. The age-and sex-adjusted odds ratio (OR) of exhibiting three or more features of the MS when carrying the À87C allele was 0.62 (P ¼ 0.04) compared to -87T/T. However, in subjects consuming less than 34.4% of energy from fat (median of fat consumption), the OR in carriers of the À87C allele was of 0.42 (P ¼ 0.008). Conclusion: These data suggest that the PPAR-delta À87T4C polymorphism may be associated with a lower risk to exhibit the MS and this association is influenced by dietary fat intake.

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Section: Discussionmentioning

confidence: 99%

Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta −87T>C polymorphism and dietary fat in French-Canadians

et al. 2006

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“…Importantly, the PPARs act as obligate heterodimers with RXR to bind PPAR response elements consisting of direct repeats of AGGTCA separated by one nucleotide (DR1). PPARs have a large, promiscuous ligand binding pocket and in addition, are subject to RXR ligand activation by 9-cis-retinoic acid and synthetic agonists (Nolte et al 1998;Xu et al 1999). …”

Section: Pparsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

Alaynick

2008

Mitochondrion

125

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Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

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“…As PPAR-g can be activated by fatty acids (Xu et al, 1999), we hypothesized that the effects of marine fatty acids on glucose metabolism could be partly mediated via PPAR-g, and therefore the common Pro12Ala polymorphism in the gene encoding for the PPAR-g2 (PPARG) might modify the associations of fatty acids with FFA and glucose levels and with insulin resistance. Earlier, the transcriptionally less active Ala-allele has been associated with enhanced insulin sensitivity (Ek et al, 2001) and antilipolytic effect of insulin (Stumvoll et al, 2001), resulting in lower FFA concentrations (Stumvoll and Häring, 2002), and with a reduced risk of TIID (Altshuler et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

The Pro12Ala polymorphism of the PPAR-γ2 gene affects associations of fish intake and marine n−3 fatty acids with glucose metabolism

Ylonen

Salminen

Lyssenko³

et al. 2007

Eur J Clin Nutr

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Background/Objectives: Data on associations between marine nÀ3 fatty acids and glucose metabolism are inconsistent. Therefore, we explored effects of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor (PPAR)-g2 gene on associations of fish intake and dietary and plasma eicosapentaenoic and docosahexaenoic acid with glucose metabolism. The design comprises of the cross-sectional analysis. Subjects/Methods: The Pro12Ala variant in the PPAR-g2 (PPARG) gene was genotyped in 571 non-diabetic relatives of subjects with type II diabetes. The dietary intake was measured by a 3-day food record, and the plasma cholesterol ester fatty acid composition was analysed with gas chromatography. Associations of dietary and plasma variables with insulin resistance and fasting and 2-h glucose and free fatty acid concentrations were analysed with multiple linear regression analysis. Results: In men, there was a significant interaction between PPARG polymorphism and plasma docosahexaenoic acid on fasting free fatty acid concentration (P ¼ 0.036), and genotype-stratified models showed an inverse association in Pro homozygotes only (P ¼ 0.028). In women, the proportion of plasma eicosapentaenoic acid was higher in Ala-allele carriers compared to Pro homozygotes (1.67 vs 1.44% respectively, P ¼ 0.006). A significant interaction between PPARG polymorphism and fish intake on 2-h glucose was found in women (P ¼ 0.021), and genotype-stratified models suggested an inverse association in Ala-allele carriers only (P ¼ 0.039). Conclusions: The findings suggest that PPARG polymorphism might affect the plasma proportion of eicosapentaenoic acid and modulate the associations of fish intake and marine nÀ3 fatty acids with glucose metabolism and fasting free fatty acids.

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Molecular Recognition of Fatty Acids by Peroxisome Proliferator–Activated Receptors

Cited by 1,033 publications

References 28 publications

Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta −87T>C polymorphism and dietary fat in French-Canadians

Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta −87T>C polymorphism and dietary fat in French-Canadians

Nuclear receptors, mitochondria and lipid metabolism

The Pro12Ala polymorphism of the PPAR-γ2 gene affects associations of fish intake and marine n−3 fatty acids with glucose metabolism

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