Evidence for Direct Binding of Fatty Acids and Eicosanoids to Human Peroxisome Proliferators-Activated Receptor α

Murakami, Koji; Ide, Tomohiro; Suzuki, Masahiro; Mochizuki, Toru; Kadowaki, Takashi

doi:10.1006/bbrc.1999.0951

Cited by 77 publications

(46 citation statements)

References 24 publications

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“…In the latter study, the K d value for (8S)-HETE was estimated to be 5-fold lower than that for Wy 14643 and 4-fold lower than that for the synthetic compound carbaprostacyclin (58). Another eicosanoid, leukotriene B 4 , was shown to be a weak ligand for mPPAR␣ and hPPAR␣ (55,59). In summary, the data in Table VII document 2 Although CYP4A11 is the human homolog of rat CYP4A8, it is presently unknown whether this enzyme catalyzes the /-1-hydroxylation of EETs.…”

Section: Table IVmentioning

confidence: 81%

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

Cowart

Wei²,

Hsu

et al. 2002

Journal of Biological Chemistry

178

152

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Cytochromes P450 of the CYP2C and CYP4A gene subfamilies metabolize arachidonic acid to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) and to 19-and 20-hydroxyeicosatetraenoic acids (HETEs), respectively. Abundant functional studies indicate that EETs and HETEs display powerful and often opposing biological activities as mediators of ion channel activity and regulators of vascular tone and systemic blood pressures. Incubation of 8,9-, 11,12-, and 14,15-EETs with microsomal and purified forms of rat CYP4A isoforms led to rapid NADPH-dependent metabolism to the corresponding 19-and 20-hydroxylated EETs. Comparisons of reaction rates and catalytic efficiency with those of arachidonic and lauric acids showed that EETs are one of the best endogenous substrates so far described for rat CYP4A isoforms. CYP4A1 exhibited a preference for 8,9-EET, whereas CYP4A2, CYP4A3, and CYP4A8 preferred 11,12-EET. In general, the closer the oxido ring is to the carboxylic acid functionality, the higher the rate of EET metabolism and the lower the regiospecificity for the EET -carbon. Analysis of cis-parinaric acid displacement from the ligand-binding domain of the human peroxisome proliferator-activated receptor-␣ showed that -hydroxylated 14,15-EET bound to this receptor with high affinity (K i ‫؍‬ 3 ؎ 1 nM). Moreover, at 1 M, the -alcohol of 14,15-EET or a 1:4 mixture of the -alcohols of 8,9-and 11,12-EETs activated human and mouse peroxisome proliferator-activated receptor-␣ in transient transfection assays, suggesting a role for them as endogenous ligands for these orphan nuclear receptors.Cytochromes P450 of the CYP4A gene subfamily are structurally and functionally conserved fatty-acid hydroxylases that are expressed in most mammalian tissues, including rat and human kidney and liver (1-7). These enzymes are selective for the /-1-hydroxylation of saturated and unsaturated fatty acids (1-7) and lack known roles in drug metabolism. The expression of some CYP4A isoforms is under the control of the peroxisome proliferator-activated receptor-␣ (PPAR␣) 1 (8 -13) and regulated by a variety of physiological and pathophysiological stimuli, including dietary fatty acids, hormones, diabetes, and starvation (9 -13). Interest in the molecular and functional properties of these enzymes has been stimulated by the demonstration of their role in the /-1-hydroxylation of arachidonic acid (AA) (4 -7) and the powerful biological activities of 19-and 20-hydroxyeicosatetraenoic acids (HETEs) as modulators of renal ion fluxes and vasoactivity (14 -18). Based on biochemical and functional correlates of CYP4A renal expression, 20-HETE biosynthesis, and the onset of systemic high blood pressure in the SHR/WKY rat model of spontaneous hypertension, a pro-hypertensive role for 20-HETE and CYP4A isoforms was proposed (14).The cytochrome P450 AA epoxygenase catalyzes the in vivo regio-and enantioselective metabolism of AA to epoxyeicosatrienoic acids (EETs) (16). Studies with microsomal and/or purified cytochrome P450 preparations showed tha...

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Section: Table IVmentioning

confidence: 81%

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

Cowart

Wei²,

Hsu

et al. 2002

Journal of Biological Chemistry

178

152

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“…The labeled oxidized metabolites and the remaining [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]AA were extracted with chloroform and resolved by reverse-phase HPLC, according to published methods (25,26) (see Materials and Methods). AA is rapidly metabolized by hepatocytes, and only 30-35% of the radioactivity remained in the organic phase as [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]AA after 1 h of incubation; however, after 6 h, only ?8% of radioactivity was still present as AA, as assessed by reverse-phase HPLC of the organic extracts (data not shown). No radioactivity was detected in the retention time corresponding to EETs, either in the presence or absence of ciprofibrate (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3), suggesting that EETs are very rapidly metabolized. For both incubation times, radioactivity was recovered mainly as [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]AA and also in metabolites eluting earlier than EETs (peak X in Fig. 3A-C).…”

Section: Resultsmentioning

confidence: 99%

P450 CYP2C epoxygenase and CYP4A ω-hydroxylase mediate ciprofibrate-induced PPARα-dependent peroxisomal proliferation

Gatica

Aguilera

Contador

et al. 2007

Journal of Lipid Research

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Peroxisomal proliferators, such as ciprofibrate, are used extensively as effective hypolipidemic drugs. The effects of these compounds on lipid metabolism require ligand binding activation of the peroxisome proliferatoractivated receptor (PPAR) a subtype of nuclear receptors and involve transcriptional activation of the metabolic pathways involved in lipid oxidative metabolism, transport, and disposition. v-Hydroxylated-eicosatrienoic acids (HEETs), products of the sequential metabolism of arachidonic acid (AA) by the cytochrome P450 CYP2C epoxygenase and CYP4A v-hydroxylase gene subfamilies, have been identified as potent and high-affinity ligands of PPARa in vitro and as PPARa activators in transient transfection assays. Using isolated rat hepatocytes in culture, we demonstrate that specific inhibition of either the CYP2C epoxygenase or the CYP4A v-hydroxylase abrogates ciprofibrate-induced peroxisomal proliferation, whereas inhibition of other eicosanoid-synthesizing pathways had no effect. Conversely, overexpression of the rat liver CYP2C11 epoxygenase leads to spontaneous peroxisomal proliferation, an effect that is reversed by a CYP inhibitor. Based on these results, we propose that HEETs may serve as endogenous PPARa ligands and that the P450 AA monooxygenases participate in ciprofibrate-induced peroxisomal proliferation and the activation of PPARa downstream targets.-Gatica, A

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“…When activated by ligand binding, PPARs can activate promoters and modulate gene expression (25,26). PGA 1 and PGA 2 are natural ligands for PPAR␣ and PPAR␥ (23,24,51,52). PGD 2 can undergo dehydration to PGJ 2 and ultimately ⌬ 12 -PGJ 2 , which is produced in significant quantities in the human body (53).…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor γ Agonists Inhibit HIV-1 Replication in Macrophages by Transcriptional and Post-transcriptional Effects

Hayes¹,

Lane²,

King³

et al. 2002

Journal of Biological Chemistry

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Evidence for Direct Binding of Fatty Acids and Eicosanoids to Human Peroxisome Proliferators-Activated Receptor α

Cited by 77 publications

References 24 publications

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

P450 CYP2C epoxygenase and CYP4A ω-hydroxylase mediate ciprofibrate-induced PPARα-dependent peroxisomal proliferation

Peroxisome Proliferator-activated Receptor γ Agonists Inhibit HIV-1 Replication in Macrophages by Transcriptional and Post-transcriptional Effects

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