Coordinate regulation of hepatic bile acid oxidation and conjugation by nuclear receptors.
Bile acids play important functions in the maintenance of bile acid homeostasis. However, due to their detergent properties, these acids are inherently cytotoxic and their accumulation in liver is associated with hepatic disorders such as cholestasis. During their enterohepatic circulation, bile acids undergo several metabolic alterations, including amidation, hydroxylation, sulfonation, and glucuronidation. Most of these transformations facilitate the excretion of bile acids into the bile (amidation and sulfonation) or into the blood for subsequent urinary elimination (hydroxylation, sulfonation, and glucuronidation). In this review, the role of various nuclear receptors and transcription factors in the expression of bile acid detoxification enzymes is summarized. In particular, the coordinate manner in which the xenobiotic sensors pregnane X receptor and constitutive androstane receptor, the lipid sensors liver X receptor, farnesoid X receptor, peroxisome proliferator-activated receptor alpha, and vitamin D receptor, and the orphan receptors hepatocyte nuclear factor 4alpha and small heterodimer partner regulate bile acid detoxification is detailed. Finally, we conclude by discussing the importance of these transcription factors as promising drug targets for the correction of cholestasis.
Trottier
Jocelyn
J
Molecular Endocrinology and Oncology Research Center, and the Faculty of Pharmacy, Laval University, Québec, Canada.
Milkiewicz
Piotr
P
Kaeding
Jenny
J
Verreault
Mélanie
M
Barbier
Olivier
O
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000201:enzymology; D000071518:Liver X Receptors; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D008954:Models, Biological; D057093:Orphan Nuclear Receptors; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated