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Lipid-activated transcription factors control bile acid glucuronidation

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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 (PPARα), 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 PPARα and LXRα in controlling human UGT1A3 expression.

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Acknowledgments

Most of the data summarized here would not have been obtained without the efficient contribution of our collaborators: members of Prof. Chantal Guillemette’s and Alain Bélanger’s laboratories (Genomic and Endocrinology Research Center, CHUQ Research Center, Laval university, Québec, Canada), of Prof. Robert H. Tukey’s lab (Laboratory of Environmental Toxicology, Department of Chemistry & Biochemistry and Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA) and of Prof. Bart Staels’ group (Unité 545, INSERM, Lille and Department of Atherosclerose, Institute Pasteur de Lille and the Faculté de Pharmacie, Université de Lille II, Lille, F-59019, France). We thank Dr. Virginie Bocher for critical reading of this manuscript. Financial support: This work was supported by the “Canadian Institutes for Health Research CIHR” (MOP 118446), the “Fonds pour la Recherche en Santé du Québec; FRSQ”. Olivier Barbier is supported by the Health Research Foundation of Rx&D-CIHR. Jenny Kaeding is holder of a scholarship from the Health Research Foundation of Rx&D-CIHR. Jocelyn Trottier is holder of a scholarship from CIHR.

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Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Endocrinology and Genomic, CHUL Research Center, Laval University, Québec, Canada

    Olivier Barbier, Jocelyn Trottier, Jenny Kaeding, Patrick Caron & Mélanie Verreault

  2. Faculty of Pharmacy, Laval University, Québec, Canada

    Olivier Barbier, Jocelyn Trottier, Jenny Kaeding, Patrick Caron & Mélanie Verreault

  3. Laboratory of Molecular Pharmacology, CHUQ-CHUL Research Center, 2705, Boulevard Laurier, Quebec, QC, G1V 4G2, Canada

    Olivier Barbier

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  1. Olivier Barbier
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  2. Jocelyn Trottier
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  5. Mélanie Verreault
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Correspondence to Olivier Barbier.

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Barbier, O., Trottier, J., Kaeding, J. et al. Lipid-activated transcription factors control bile acid glucuronidation. Mol Cell Biochem 326, 3–8 (2009). https://doi.org/10.1007/s11010-008-0001-5

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  • DOI: https://doi.org/10.1007/s11010-008-0001-5

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