Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity

Grace L. Guo, Gilles Lambert, Masahiko Negishi, Jerrold M. Ward, H. Bryan Brewer, Steven A. Kliewer, Frank J. Gonzalez, Christopher J. Sinal

Research output: Contribution to journalArticle

234 Citations (Scopus)

Abstract

The nuclear receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR), are important in maintaining bile acid homeostasis. Deletion of both FXR and PXR in vivo by cross-breeding B6;129-FxrtmlGonz (FXR-null) and B6;129-PxrtmlGlaxo-Wellcome (PXR-null) mice revealed a more severe disruption of bile acid, cholesterol, and lipid homeostasis in B6;129-Fxr tmlGonz PxrtmlGlaxo-Wellcome (FXR-PXR double null or FPXR-null) mice fed a 1% cholic acid (CA) diet. Hepatic expression of the constitutive androstane receptor (CAR) and its target genes was induced in FXR- and FPXR-null mice fed the CA diet. To test whether up-regulation of CAR represents a means of protection against bile acid toxicity to compensate for the loss of FXR and PXR, animals were pretreated with CAR activators, phenobarbital or 1,4-bis[2-(3,5-dichlorpyridyloxy)]benzene (TCPOBOP), followed by the CA diet. A role for CAR in protection against bile acid toxicity was confirmed by a marked reduction of serum bile acid and bilirubin concentrations, with an elevation of the expression of the hepatic genes involved in bile acid and/or bilirubin metabolism and excretion (CYP2B, CYP3A, MRP2, MRP3, UGT1A, and glutathione S-transferase α), following pretreatment with phenobarbital or TCPOBOP. In summary, the current study demonstrates a critical and combined role of FXR and PXR in maintaining not only bile acid but also cholesterol and lipid homeostasis in vivo. Furthermore, FXR, PXR, and CAR protect against hepatic bile acid toxicity in a complementary manner, suggesting that they serve as redundant but distinct layers of defense to prevent overt hepatic damage by bile acids during cholestasis.

Original languageEnglish (US)
Pages (from-to)45062-45071
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number46
DOIs
StatePublished - Nov 14 2003

Fingerprint

Bile Acids and Salts
Toxicity
Cholic Acid
Nutrition
Homeostasis
Liver
Phenobarbital
Diet
Bilirubin
Genes
Cholesterol
Lipids
pregnane X receptor
constitutive androstane receptor
Cytochrome P-450 CYP3A
Cholestasis
Cytoplasmic and Nuclear Receptors
Benzene
Glutathione Transferase
Metabolism

ASJC Scopus subject areas

  • Biochemistry

Cite this

Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity. / Guo, Grace L.; Lambert, Gilles; Negishi, Masahiko; Ward, Jerrold M.; Brewer, H. Bryan; Kliewer, Steven A.; Gonzalez, Frank J.; Sinal, Christopher J.

In: Journal of Biological Chemistry, Vol. 278, No. 46, 14.11.2003, p. 45062-45071.

Research output: Contribution to journalArticle

Guo, Grace L. ; Lambert, Gilles ; Negishi, Masahiko ; Ward, Jerrold M. ; Brewer, H. Bryan ; Kliewer, Steven A. ; Gonzalez, Frank J. ; Sinal, Christopher J. / Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 46. pp. 45062-45071.
@article{34216a02754f4bc78e3a0f481374104a,
title = "Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity",
abstract = "The nuclear receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR), are important in maintaining bile acid homeostasis. Deletion of both FXR and PXR in vivo by cross-breeding B6;129-FxrtmlGonz (FXR-null) and B6;129-PxrtmlGlaxo-Wellcome (PXR-null) mice revealed a more severe disruption of bile acid, cholesterol, and lipid homeostasis in B6;129-Fxr tmlGonz PxrtmlGlaxo-Wellcome (FXR-PXR double null or FPXR-null) mice fed a 1{\%} cholic acid (CA) diet. Hepatic expression of the constitutive androstane receptor (CAR) and its target genes was induced in FXR- and FPXR-null mice fed the CA diet. To test whether up-regulation of CAR represents a means of protection against bile acid toxicity to compensate for the loss of FXR and PXR, animals were pretreated with CAR activators, phenobarbital or 1,4-bis[2-(3,5-dichlorpyridyloxy)]benzene (TCPOBOP), followed by the CA diet. A role for CAR in protection against bile acid toxicity was confirmed by a marked reduction of serum bile acid and bilirubin concentrations, with an elevation of the expression of the hepatic genes involved in bile acid and/or bilirubin metabolism and excretion (CYP2B, CYP3A, MRP2, MRP3, UGT1A, and glutathione S-transferase α), following pretreatment with phenobarbital or TCPOBOP. In summary, the current study demonstrates a critical and combined role of FXR and PXR in maintaining not only bile acid but also cholesterol and lipid homeostasis in vivo. Furthermore, FXR, PXR, and CAR protect against hepatic bile acid toxicity in a complementary manner, suggesting that they serve as redundant but distinct layers of defense to prevent overt hepatic damage by bile acids during cholestasis.",
author = "Guo, {Grace L.} and Gilles Lambert and Masahiko Negishi and Ward, {Jerrold M.} and Brewer, {H. Bryan} and Kliewer, {Steven A.} and Gonzalez, {Frank J.} and Sinal, {Christopher J.}",
year = "2003",
month = "11",
day = "14",
doi = "10.1074/jbc.M307145200",
language = "English (US)",
volume = "278",
pages = "45062--45071",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "46",

}

TY - JOUR

T1 - Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity

AU - Guo, Grace L.

AU - Lambert, Gilles

AU - Negishi, Masahiko

AU - Ward, Jerrold M.

AU - Brewer, H. Bryan

AU - Kliewer, Steven A.

AU - Gonzalez, Frank J.

AU - Sinal, Christopher J.

PY - 2003/11/14

Y1 - 2003/11/14

N2 - The nuclear receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR), are important in maintaining bile acid homeostasis. Deletion of both FXR and PXR in vivo by cross-breeding B6;129-FxrtmlGonz (FXR-null) and B6;129-PxrtmlGlaxo-Wellcome (PXR-null) mice revealed a more severe disruption of bile acid, cholesterol, and lipid homeostasis in B6;129-Fxr tmlGonz PxrtmlGlaxo-Wellcome (FXR-PXR double null or FPXR-null) mice fed a 1% cholic acid (CA) diet. Hepatic expression of the constitutive androstane receptor (CAR) and its target genes was induced in FXR- and FPXR-null mice fed the CA diet. To test whether up-regulation of CAR represents a means of protection against bile acid toxicity to compensate for the loss of FXR and PXR, animals were pretreated with CAR activators, phenobarbital or 1,4-bis[2-(3,5-dichlorpyridyloxy)]benzene (TCPOBOP), followed by the CA diet. A role for CAR in protection against bile acid toxicity was confirmed by a marked reduction of serum bile acid and bilirubin concentrations, with an elevation of the expression of the hepatic genes involved in bile acid and/or bilirubin metabolism and excretion (CYP2B, CYP3A, MRP2, MRP3, UGT1A, and glutathione S-transferase α), following pretreatment with phenobarbital or TCPOBOP. In summary, the current study demonstrates a critical and combined role of FXR and PXR in maintaining not only bile acid but also cholesterol and lipid homeostasis in vivo. Furthermore, FXR, PXR, and CAR protect against hepatic bile acid toxicity in a complementary manner, suggesting that they serve as redundant but distinct layers of defense to prevent overt hepatic damage by bile acids during cholestasis.

AB - The nuclear receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR), are important in maintaining bile acid homeostasis. Deletion of both FXR and PXR in vivo by cross-breeding B6;129-FxrtmlGonz (FXR-null) and B6;129-PxrtmlGlaxo-Wellcome (PXR-null) mice revealed a more severe disruption of bile acid, cholesterol, and lipid homeostasis in B6;129-Fxr tmlGonz PxrtmlGlaxo-Wellcome (FXR-PXR double null or FPXR-null) mice fed a 1% cholic acid (CA) diet. Hepatic expression of the constitutive androstane receptor (CAR) and its target genes was induced in FXR- and FPXR-null mice fed the CA diet. To test whether up-regulation of CAR represents a means of protection against bile acid toxicity to compensate for the loss of FXR and PXR, animals were pretreated with CAR activators, phenobarbital or 1,4-bis[2-(3,5-dichlorpyridyloxy)]benzene (TCPOBOP), followed by the CA diet. A role for CAR in protection against bile acid toxicity was confirmed by a marked reduction of serum bile acid and bilirubin concentrations, with an elevation of the expression of the hepatic genes involved in bile acid and/or bilirubin metabolism and excretion (CYP2B, CYP3A, MRP2, MRP3, UGT1A, and glutathione S-transferase α), following pretreatment with phenobarbital or TCPOBOP. In summary, the current study demonstrates a critical and combined role of FXR and PXR in maintaining not only bile acid but also cholesterol and lipid homeostasis in vivo. Furthermore, FXR, PXR, and CAR protect against hepatic bile acid toxicity in a complementary manner, suggesting that they serve as redundant but distinct layers of defense to prevent overt hepatic damage by bile acids during cholestasis.

UR - http://www.scopus.com/inward/record.url?scp=0242665373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0242665373&partnerID=8YFLogxK

U2 - 10.1074/jbc.M307145200

DO - 10.1074/jbc.M307145200

M3 - Article

C2 - 12923173

AN - SCOPUS:0242665373

VL - 278

SP - 45062

EP - 45071

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 46

ER -