Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity.
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-Fxrtm1Gonz (FXR-null) and B6;129-Pxrtm1Glaxo-Wellcome (PXR-null) mice revealed a more severe disruption of bile acid, cholesterol, and lipid homeostasis in B6;129-Fxrtm1Gonz Pxrtm1Glaxo-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 alpha), 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.
Guo
Grace L
GL
Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lambert
Gilles
G
Negishi
Masahiko
M
Ward
Jerrold M
JM
Brewer
H Bryan
HB
Kliewer
Steven A
SA
Gonzalez
Frank J
FJ
Sinal
Christopher J
CJ
D000821:Animal Feed; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism; D001692:Biological Transport; D015152:Blotting, Northern; D001835:Body Weight; D002467:Cell Nucleus / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003001:Cloning, Molecular; D000090702:Constitutive Androstane Receptor; D003433:Crosses, Genetic; D051544:Cytochrome P-450 CYP3A; D004268:DNA-Binding Proteins / Q000502:physiology*; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010634:Phenobarbital / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D000077297:Pregnane X Receptor; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D012269:Ribosomal Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated
D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts; D001663:Bilirubin; D002784:Cholesterol; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D004268:DNA-Binding Proteins; D005982:Glutathione Transferase; D024101:Mitochondrial Proteins; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital; D010743:Phospholipids; D000077297:Pregnane X Receptor; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C093947:MRP2 protein, S cerevisiae; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene