title: Lipid-activated transcription factors control bile acid glucuronidation.
abstract: Bile acids subserve important physiological functions in the control of cholesterol homeostasis. Indeed, hepatic bile acid synthesis and biliary excretion constitute the main route for cholesterol removal from the human body. On the other hand, bile acids serve as natural detergents for the intestinal absorption of dietary cholesterol. However, due to their detergent properties, bile acids are inherently cytotoxic, and their cellular level may be tightly controlled to avoid pathological situations such as cholestasis. Recent investigations have illustrated the crucial roles that a series of ligand-activated transcription factors has in the control of hepatic bile acids synthesis, transport and metabolism. Thus, the lipid-activated nuclear receptors, farnesoid X-receptor (FXR), liver X-receptor (LXR), pregnane X-receptor (PXR) and peroxisome proliferator-activated receptor alpha (PPAR alpha), modulate the expression and activity of genes controlling bile acid homeostasis in the liver. Several members of the UDP-glucuronosyltransferase (UGT) enzymes family are among the bile acid metabolizing enzymes regulated by these receptors. UGTs catalyze glucuronidation, a major phase II metabolic reaction, which converts hydrophobic bile acids into polar and urinary excretable metabolites. This article summarizes our recent observations on the regulation of bile acid conjugating UGTs upon pharmacological activation of lipid-activated receptors, with a particular interest for the role of PPAR alpha and LXRalpha in controlling human UGT1A3 expression.
authors.affiliation: Laboratory of Molecular Pharmacology, Endocrinology and Genomic, CHUL Research Center, Laval University, Québec, Canada. olivier.barbier@pha.ulaval.ca
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Trottier
authors.forename: Jenny
authors.initials: J
authors.lastname: Kaeding
authors.forename: Patrick
authors.initials: P
authors.lastname: Caron
authors.forename: Mélanie
authors.initials: M
authors.lastname: Verreault
mesh_terms: D001647:Bile Acids and Salts / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008954:Models, Biological; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000378:metabolism*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D008055:Lipids; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014453:Glucuronosyltransferase