Regulation of endobiotics glucuronidation by ligand-activated transcription factors: physiological function and therapeutic potential

Abstract

Recent progresses in molecular pharmacology approaches have allowed the identification and characterization of a series of nuclear receptors (NR) which efficiently control the level UDP-glucuronosyltransferase (UGT) genes expression. These regulatory processes ensure optimized UGT expression in response to specific endogenous and/or exogenous stimuli. Interestingly, numerous endogenous activators of these NRs are conjugated by the UGT enzymes they regulate. In such a case, the NR-dependent regulation of UGT genes corresponds to a feedforward/feedback mechanism by which a bioactive molecule controls its own concentrations. In the present review, we will discuss i) how bilirubin reduces its circulating levels by activating AhR in the liver; ii) how bile acids modulate their hepatic glucuronidation via PXR- and FXR-dependent processes in enterohepatic tissues; and iii) how androgens inhibit their cellular metabolism in prostate cancer cells through an AR-dependent mechanism. Subsequently, with further discussion of the same examples (bilirubin and bile acids), we will illustrate how NR-dependent regulation of UGT enzymes may contribute to the beneficial effects of pharmacological activators of nuclear receptors, such as CAR and PPARa.

PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis

“…We thus checked whether the expression and activity of UGTs in the small intestine are elevated. The hepatic expression of Ugts has been previously been shown to play an important role in the metabolic elimination of bile acids202122. However, very little is known about the role of intestinal UGTs in determining the homeostasis of bile acids.…”

“…Instead, these results strongly indicate that the glucuronidation of bile acids in colitis mice is drastically increased, which may explain the reduced intracellular levels of uncojungated bile acids. Unlike taurine- and glycine-conjugated bile acids, glucuronidated bile acids cannot be reabsorbed and may represent an important detoxification mechanism under the condition of abnormal bile acids accumulation21. Previous studies suggested that the hepatic glucuronidation of bile acids may be part of a negative feedback mechanism by which bile acids limit their biological activity and control their intracellular level to avoid a pathophysiological accumulation2340.…”

The Human UDP-Glucuronosyltransferase UGT2A1 and UGT2A2 Enzymes Are Highly Active in Bile Acid Glucuronidation

“…Among the human UGT1A and UGT2B, UGT1A3, UGT2B4, and UGT2B7 have a capacity to convert BAs into BA glucuronides (BA-G) in vitro. UGT1A3 is the major enzyme for hepatic production of BA-24G, and UGT2B4 and UGT2B7 are the main producers of ether glucuronides (Pillot et al, 1993;Gall et al, 1999;Trottier et al, 2006;Court et al, 2008;Verreault et al, 2010). We compared the activity of UGT2A enzymes UGT2A1 and UGT2A2 Glucuronidate Bile Acids in conjugating six BA species found as glucuronide derivatives in the human blood (Trottier et al, 2012).…”

“…Glucuronide conjugates represent up to 10% of the BA circulating pool in healthy volunteers (Trottier et al, 2012), and their formation involves either the 3/6-hydroxyl or 24-carboxyl group of the BA steroid nucleus for the respective formation of ether 3/6G or acyl/ester 24G (Gall et al, 1999;Caron et al, 2006;Trottier et al, 2006Trottier et al, , 2012Court et al, 2008;Verreault et al, 2010). Among the human UGT1A and UGT2B, UGT1A3, UGT2B4, and UGT2B7 have a capacity to convert BAs into BA glucuronides (BA-G) in vitro.…”

Pleiotropic Functions of the Organic Solute Transporter Ostα-Ostβ

“…Because DHEAS and PREGS are also major excitatory neurosteroids, these ob- Bile acids can signal to the cell via two major receptors, the nuclear receptor FXR, and GPBAR-1/TGR5 [17][18][19][20][21][22][23] . The latter is a membrane-bound G-protein-coupled receptor that can mediate the rapid, transcription-independent actions of bile acids.…”