Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid–Mediated Changes in Plasma Lipoprotein Profile

Masson, David; Lagrost, Laurent; Athias, Anne; Gambert, Philippe; Brimer-Cline, Cynthia; Lan, Lu‐Bin; Schuetz, John D.; Schuetz, Erin G.; Assem, Mahfoud

doi:10.1161/01.atv.0000183674.88817.fb

Cited by 34 publications

(23 citation statements)

References 46 publications

(43 reference statements)

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“…Our finding that rifampicinactivated PXR regulates HDL metabolism is consistent with a recent report that the induction of CYP3A4 is correlated with increased plasma HDL and apoA-I levels and that rifampicin and other PXR agonists increase apoA-I expression and serum HDL-cholesterol levels in rodents (33). Our results may suggest an indirect mechanism for the PXR regulation of HDL metabolism via the induction of CYP27A1 and activation of the LXRa target genes ABCA1 and ABCG1 in intestine cells (41).…”

Section: Discussionsupporting

confidence: 92%

“…Bile acids are known to reduce HDL cholesterol, plasma apoA-I, and hepatic apoA-I mRNA expression in wild-type mice (39,40). The inhibitory effect of bile acids is more pronounced in Pxr null mice and is attenuated in human PXR transgenic mice (41). It was suggested that PXR might antagonize the inhibitory effect of the bile acid receptor farnesoid X receptor on apoA-I mRNA expression and HDL metabolism and that bile acids may induce ABCA1 and ABCG1 gene transcription (42).…”

Section: Discussionmentioning

confidence: 99%

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PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine

Chen

Chiang

2007

Journal of Lipid Research

102

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Mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes oxidative cleavage of the sterol side chain in the bile acid biosynthetic pathway in the liver and 27-hydroxylation of cholesterol in most tissues. Recent studies suggest that 27-hydroxycholesterol (27-HOC) activates liver orphan receptor a (LXRa) and induces the cholesterol efflux transporters ABCA1 and ABCG1 in macrophages. The steroid-and bile acid-activated pregnane X receptor (PXR) plays critical roles in the detoxification of bile acids, cholesterol metabolites, and xenobiotics. The role of CYP27A1 in the intestine is not known. This study investigated PXR and CYP27A1 regulation of cholesterol metabolism in the human intestinal cell lines Caco2 and Ls174T. A human PXR ligand, rifampicin, induced CYP27A1 mRNA expression in intestine cells but not in liver cells. Rifampicin induced CYP27A1 gene transcription, increased intracellular 27-HOC levels, and induced ABCA1 and ABCG1 mRNA expression only in intestine cells. A functional PXR binding site was identified in the human CYP27A1 gene. Chromatin immunoprecipitation assays revealed that rifampicin induced the PXR recruitment of steroid receptor coactivator 1 to CYP27A1 chromatin. Cholesterol loading markedly increased intracellular 27-HOC levels in intestine cells. Rifampicin, 27-HOC, and a potent LXRa agonist, T0901317, induced ABCA1 and ABCG1 protein expression and stimulated cholesterol efflux from intestine cells to apolipoprotein A-I and HDL. This study suggests an intestine-specific PXR/CYP27A1/LXRa pathway that regulates intestine cholesterol efflux and HDL assembly.-Li, T., W. Chen, and J. Y. L. Chiang. PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine. J. Lipid Res.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine

Chen

Chiang

2007

Journal of Lipid Research

102

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“…Interestingly, were not reported. Interestingly, expression of human PXR in mice antagonizes cholic acid-mediated downregulation of plasma HDL levels and hepatic Apo-AI expression, which was attributed to repressed farnesyl X receptor activity by PXR ( 42 ). Albeit that different mechanisms may contribute to PXR-mediated effects on plasma lipid and lipoprotein levels in different animal models, all of this evidence suggests that activation of PXR can affect cholesterol metabolism and may play a role in atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice

Zhou

King

Chen

et al. 2009

Journal of Lipid Research

133

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“…The understanding of Sirt1 regulation of PXR function [14] in xenobiotics metabolism is now required with important involvement of PXR in HDL cholesterol metabolism [124] [125]. Furthermore, the involvement of PXR in the diabetes has increased with the involvement of various PXR agonists in glucose and lipid dysregulation [126] [127].…”

Section: Endocrine Disruptors As Risk Factors For Obesity and Chronicmentioning

confidence: 99%

Induction of NAFLD with Increased Risk of Obesity and Chronic Diseases in Developed Countries

Martins¹

2014

OJEMD

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The susceptibility of individuals to obesity has been reported in many developed countries with predisposition of humans to obesity associated with high calorie diets and unhealthy lifestyles. Obesity may closely be involved in cell suicide in various organ diseases with the importance of accelerated aging that requires early intervention with drug therapy to prevent diseases such as non alcoholic fatty liver disease (NAFLD) that has increased in children and reached to approx. 40% of the global population. Obesity is induced by various diets and lifestyle factors such as stress, anxiety and depression which are important to consider with the global increase in obesity and are possibly linked to the rise in individuals with brain disorders that involve neurodegeneration. Xenobiotics such as the endocrine disruptor chemicals that have increased in the environment in various developed countries lead to various chronic endocrine diseases as populations divert towards unhealthy diets and lifestyles with induction of NAFLD and obesity. The amount and nature of food intake that improves and increases liver lipid and xenobiotic metabolism in obese individuals have become important to decrease the risk for increased adiposity in man. High fibre or protein diets that contain leucine may improve liver glucose, lipid and xenobiotic metabolism and require further investigation with xenobiotics such as endocrine disruptors involved in appetite dysregulation and metabolic disorders in developed countries. The use of anti-obese drugs that reduce food intake and improve hypercholesterolemia and cardiovascular disease has been assessed in obesity with drug therapy closely involved either in the prevention or induction of NAFLD and obesity in man.

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Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid–Mediated Changes in Plasma Lipoprotein Profile

Cited by 34 publications

References 46 publications

PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine

PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine

Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice

Induction of NAFLD with Increased Risk of Obesity and Chronic Diseases in Developed Countries

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