Cyp3a Induction by Liver X Receptor Ligands in Primary Cultured Rat and Mouse Hepatocytes Is Mediated by the Pregnane X Receptor

Shenoy, Sarita D.; Spencer, Thomas A.; Mercer-Haines, Nancy A.; Alipour, Masumeh; Gargano, Mary; Runge‐Morris, Melissa; Kocarek, Thomas A.

doi:10.1124/dmd.32.1.66

Cited by 73 publications

(47 citation statements)

References 38 publications

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“…Based on these observations, and considering the remarkable correlation between hepatic cholesterol levels and Cyp3a11 expression, we evaluated the potential of several hydroxylated derivatives of cholesterol to activate mouse PXR in cell culture. 24(S),25-Epoxycholesterol was a good activator of mouse PXR in our system, in accordance with previous observations in mouse hepatocytes (39). Interestingly, 25-and 27-hydroxycholesterol efficiently activated murine PXR as well.…”

Section: Discussionsupporting

confidence: 80%

“…PCN, a known potent activator of murine PXR used as a positive control, led to 18-fold activation of the reporter gene activity over vehicle-treated cells. In addition, hydroxylated derivatives of cholesterol, like the potent LXR agonist 24(S),25-epoxycholesterol, also could activate PXR, confirming previous observations in mouse hepatocytes (39). 22(R)-Hydroxycholesterol displayed only weak activation of PXR, whereas 22(S)-hydroxycholesterol was inactive.…”

Section: Cholesterol Derivatives Are Activators Of Mouse Pxrsupporting

confidence: 74%

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LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver

Gnerre

Schuster

Roth

et al. 2005

Journal of Lipid Research

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Section: Discussionsupporting

confidence: 80%

Section: Cholesterol Derivatives Are Activators Of Mouse Pxrsupporting

confidence: 74%

LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver

Gnerre

Schuster

Roth

et al. 2005

Journal of Lipid Research

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“…Several bile acid and cholesterol metabolites produced in the bile acid synthesis and cholesterol/oxysterol synthesis pathways are potent endogenous PXR ligands (20)(21)(22)(23). Bile acids are known to reduce HDL cholesterol, plasma apoA-I, and hepatic apoA-I mRNA expression in wild-type mice (39,40).…”

Section: Discussionmentioning

confidence: 99%

“…Oxysterols and cholesterol metabolites are able to activate PXR and induce Cyp3a in rat and mouse hepatocytes (20,21). A bile acid metabolite, 5b-cholestane-3a,7a,12a-triol, is a substrate of both Cyp3a11 and Cyp27a1 and has been identified as a PXR ligand in mouse liver (22,23).…”

mentioning

confidence: 99%

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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“…75) and pregnane X receptor (PXR; ref. 76), to ensure that the effects we observed were caused by LXR-dependent mechanisms, we switched to the more specific agonist GW3965 and continued the supplementation with 9-cis retinoic acid. Thus, for the assays described below, primary immature DCs were first incubated overnight with DMSO vehicle only or with 5 μM GW3965 and 1 μM 9-cis retinoic acid.…”

Section: Human Monocyte-derived Dcsmentioning

confidence: 99%

LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression

Feig¹,

Pineda-Torra²,

Sanson³

et al. 2010

J. Clin. Invest.

160

161

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We have previously shown that mouse atherosclerosis regression involves monocyte-derived (CD68 + ) cell emigration from plaques and is dependent on the chemokine receptor CCR7. Concurrent with regression, mRNA levels of the gene encoding LXRα are increased in plaque CD68 + cells, suggestive of a functional relationship between LXR and CCR7. To extend these results, atherosclerotic Apoe -/-mice sufficient or deficient in CCR7 were treated with an LXR agonist, resulting in a CCR7-dependent decrease in plaque CD68 + cells. To test the requirement for LXR for CCR7-dependent regression, we transplanted aortic arches from atherosclerotic Apoe -/-mice, or from Apoe -/-mice with BM deficiency of LXRα or LXRβ, into WT recipients. Plaques from both LXRα-and LXRβ-deficient Apoe -/-mice exhibited impaired regression. In addition, the CD68 + cells displayed reduced emigration and CCR7 expression. Using an immature DC line, we found that LXR agonist treatment increased Ccr7 mRNA levels. This increase was blunted when LXRα and LXRβ levels were reduced by siRNAs. Moreover, LXR agonist treatment of primary human immature DCs resulted in functionally significant upregulation of CCR7. We conclude that LXR is required for maximal effects on plaque CD68 + cell expression of CCR7 and monocyte-derived cell egress during atherosclerosis regression in mice.

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Cyp3a Induction by Liver X Receptor Ligands in Primary Cultured Rat and Mouse Hepatocytes Is Mediated by the Pregnane X Receptor

Cited by 73 publications

References 38 publications

LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver

LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver

PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine

LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression

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