Evidence for a new human CYP1A1 regulation pathway involving PPAR-α and 2 PPRE sites

Sérée, Eric; Villard, Pierre-Henri; Pascussi, Jean‐Marc; Pineau, Thierry; Maurel, Patrick; Nguyen, Q.B.; Fallone, Frédérique; Martin, Pièrre‐Marie; Champion, Serge; Lacarelle, Bruno; Savouret, Jean‐François; Barra, Yves

doi:10.1053/j.gastro.2004.08.023

Cited by 79 publications

(23 citation statements)

References 27 publications

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“…Collectively, these results provide a possible mechanism for AhR and BMAL1 to regulate PPAR-α. Because PPAR-α regulates BMAL1, AhR, and CYP1A1 (Canaple et al 2006; Seree et al 2004; Villard et al 2007), we speculate that the inhibitory effect of Bmal1 silencing on AhR and CYP1A1 may be mediated by PPAR-α. Similarly, the reduction in BMAL1 caused by Ahr silencing may depend on PPAR-α.…”

Section: Discussionmentioning

confidence: 93%

Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-α Pathway Activity in Mice

Wang

Krager

et al. 2011

Environ Health Perspect

116

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Background: Numerous man-made pollutants activate the aryl hydrocarbon receptor (AhR) and are risk factors for type 2 diabetes. AhR signaling also affects molecular clock genes to influence glucose metabolism.Objective: We investigated mechanisms by which AhR activation affects glucose metabolism.Methods: Glucose tolerance, insulin resistance, and expression of peroxisome proliferator–activated receptor-α (PPAR-α) and genes affecting glucose metabolism or fatty acid oxidation and clock gene rhythms were investigated in wild-type (WT) and AhR-deficient [knockout (KO)] mice. AhR agonists and small interfering RNA (siRNA) were used to examine the effect of AhR on PPAR-α expression and glycolysis in the liver cell line Hepa-1c1c7 (c7) and its c12 and c4 derivatives. Brain, muscle ARNT-like protein 1 (Bmal1) siRNA and Ahr or Bmal1 expression plasmids were used to analyze the effect of BMAL1 on PPAR-α expression in c7 cells.Results: KO mice displayed enhanced insulin sensitivity and improved glucose tolerance, accompanied by decreased PPAR-α and key gluconeogenic and fatty acid oxidation enzymes. AhR agonists increased PPAR-α expression in c7 cells. Both Ahr and Bmal1 siRNA reduced PPAR-α and metabolism genes. Moreover, rhythms of BMAL1 and blood glucose were altered in KO mice.Conclusions: These results indicate a link between AhR signaling, circadian rhythms, and glucose metabolism. Furthermore, hepatic activation of the PPAR-α pathway provides a mechanism underlying AhR-mediated insulin resistance.

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Section: Discussionmentioning

confidence: 93%

Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-α Pathway Activity in Mice

Wang

Krager

et al. 2011

Environ Health Perspect

116

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“…In particular, the analysis of ROS and steroid biosynthesis revealed that ROS generated by MEHP affects testicular steroidogenesis via the Cyp1a1 gene and its gene network. Activation of the PPAR family of transcription factors by MEHP could target the two PPAR response elements in the Cyp1a1 gene (78). The mechanism by which MEHP acts to inhibit steroidogenesis in MA-10 cells might apply more broadly because a number of endocrine disruptors in the environment generate ROS.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Mediating the Effect of Mono-(2-Ethylhexyl) Phthalate on Hormone-Stimulated Steroidogenesis in MA-10 Mouse Tumor Leydig Cells

Fan

Traore

et al. 2010

Endocrinology

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Di-(2-ethylhexyl) phthalate, a widely used plasticizer, and its active metabolite, mono-(2-ethylhexyl) phthalate (MEHP), have been shown to exert adverse effects on the reproductive tract in developing and adult animals. As yet, however, the molecular mechanisms by which they act are uncertain. In the present study, we address the molecular and cellular mechanisms underlying the effects of MEHP on basal and human chorionic gonadotropin (hCG)-stimulated steroid production by MA-10 Leydig cells, using a systems biology approach. MEHP induced dose-dependent decreases in hCG-stimulated steroid formation. Changes in mRNA and protein expression in cells treated with increasing concentrations of MEHP in the presence or absence of hCG were measured by gene microarray and protein high-throughput immunoblotting analyses, respectively. Expression profiling indicated that low concentrations of MEHP induced the expression of a number of genes that also were expressed after hCG stimulation. Cross-comparisons between the hCG and MEHP treatments revealed two genes, Anxa1 and AR1. We suggest that these genes may be involved in a new self-regulatory mechanism of steroidogenesis. The MEHP-induced decreases in hCG-stimulated steroid formation were paralleled by increases in reactive oxygen species generation, with the latter mediated by the Cyp1a1 gene and its network. A model for the mechanism of MEHP action on MA-10 Leydig cell steroidogenesis is proposed.

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“…Furthermore, several nuclear receptors are involved in the upregulation of hCYP1A1 ; for example, the constitutive androstane receptor (CAR) [37] which is also a regulator of the expression of the CYP2A, 2B, 2C, and 3A subfamilies is activated by drugs; the liver X receptor α (LXR α ) that is involved in lipid homeostasis is activated by oxysterols [38, 39]; and the peroxisome proliferator-activated receptor α (PPAR α ), is activated by fibrates, phthalates, arachidonic acid, and its derivatives [40, 41]. These receptors bind to their specific responsive elements located in the gene promoter, activate the transcription, and potentiate the induction of hCYP1A1 .…”

Section: Upregulation Of Cyp1a1mentioning

confidence: 99%

Regulation of Human Cytochrome P4501A1 (hCYP1A1): A Plausible Target for Chemoprevention?

Santes-Palacios¹,

Ornelas-Ayala²,

Cabañas³

et al. 2016

BioMed Research International

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Human cytochrome P450 1A1 (hCYP1A1) has been an object of study due to its role in precarcinogen metabolism; for this reason it is relevant to know more in depth the mechanisms that rule out its expression and activity, which make this enzyme a target for the development of novel chemiopreventive agents. The aim of this work is to review the origin, regulation, and structural and functional characteristics of CYP1A1 letting us understand its role in the bioactivation of precarcinogen and the consequences of its modulation in other physiological processes, as well as guide us in the study of this important protein.

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Evidence for a new human CYP1A1 regulation pathway involving PPAR-α and 2 PPRE sites

Cited by 79 publications

References 27 publications

Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-α Pathway Activity in Mice

Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-α Pathway Activity in Mice

Molecular Mechanisms Mediating the Effect of Mono-(2-Ethylhexyl) Phthalate on Hormone-Stimulated Steroidogenesis in MA-10 Mouse Tumor Leydig Cells

Regulation of Human Cytochrome P4501A1 (hCYP1A1): A Plausible Target for Chemoprevention?

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