Coordinate Regulation of Hepatic Bile Acid Oxidation and Conjugation by Nuclear Receptors

Abstract

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 4α 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. Keywords: Nuclear receptor; bile acid metabolism; cholestasis; amidation; oxidation; glucuronidation; sulfonation

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

“…[69][70]Bile acid conjugation to glycine or taurine increases bile acid solubility, renders the bile acids impermeable to cell membranes and is essential to proper liver function [69]. In addition, β-citrylglutamate may have a role in spermatogenesis [54] and in the differentiation of lens epithelial cells into fiber cells [70].…”

The liver X-receptor alpha controls hepatic expression of the human bile acid-glucuronidating UGT1A3 enzyme in human cells and transgenic mice

“…9 In humans, nine UGT1A proteins, issued from a single gene located on chromosome 2q37, have been characterized, 9 among which the UGT1A3 isoform has recently been reported as an important BA glucuronidating enzyme. 10,11 UGT1A3 catalyzes the hepatic formation of acyl conjugates such as the CDCA-24G and LCA-24G 10 (Trottier et al, unpublished results).…”

Phase 1 and Phase 2 Drug Metabolism and Bile Acid Production of HepaRG Cells in a Bioartificial Liver in Absence of Dimethyl Sulfoxide

“…The HepaRG-AMC-BAL has the capacity to hydroxylate bile acids, which is a CYP3A function, and to conjugate them with taurine, which is catalyzed by the enzymes bile acid CoA synthetase and bile acid-CoA:amino acid N-acetyltransferase (Trottier et al, 2006). The latter two enzymes are controlled by nuclear receptors farnesoid X receptor and peroxisome proliferator-activated receptor alpha (Trottier et al, 2006).…”

“…The latter two enzymes are controlled by nuclear receptors farnesoid X receptor and peroxisome proliferator-activated receptor alpha (Trottier et al, 2006). These two transcription factors are also thought to play a role in the coordinate expression of UGTs and hepatic transporters as basic elements of hepatic drug metabolism.…”