Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury.
Cholestasis is associated with accumulation of bile acids and lipids, and liver injury. The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors that coordinate protective hepatic responses to potentially toxic stimuli, including bile acids. We investigated the role of these receptors in the regulation of bile acid and lipid metabolism in a bile duct ligation (BDL) model of cholestasis applied to receptor knockout mice. Hepatic damage from bile acid accumulation was increased in both CAR knockout (CARKO) and PXR knockout mice, but bile acid concentrations were lower in CARKO mice. High-density lipoprotein (HDL) cholesterol was elevated in CARKO mice, and serum total cholesterol increased less in CARKO or PXR knockout mice than WT mice after BDL. Gene expression analysis of the BDL knockout animals demonstrated that, in response to cholestasis, PXR and CAR both repressed and induced the specific hepatic membrane transporters Oatp-c (organic anion transporting polypeptide C) and Oatp2 (Na+-dependent organic anion transporter 2), respectively. Induction of the xenobiotic transporter multidrug resistance protein 1 in cholestasis was independent of either PXR or CAR, in contrast to the known pattern of induction of multidrug resistance protein 1 by xenobiotics. These results demonstrate that CAR and PXR influence cholesterol metabolism and bile acid synthesis, as well as multiple detoxification pathways, and suggest their potential role as therapeutic targets for the treatment of cholestasis and lipid disorders.
Stedman
Catherine A M
CA
Department of Clinical Pharmacology, University of Sydney, Sydney, New South Wales 2006, Australia.
Liddle
Christopher
C
Coulter
Sally A
SA
Sonoda
Junichiro
J
Alvarez
Jacqueline G A
JG
Moore
David D
DD
Evans
Ronald M
RM
Downes
Michael
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000601:surgery; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D027381:Liver-Specific Organic Anion Transporter 1; C464433:Oatp2 protein, mouse; D027701:Organic Cation Transport Proteins; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D002784:Cholesterol