Elucidating the differential contribution of sulfonation and glucuronidation in controlling nuclear receptor activity.

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Rationale: Glucuronidation and sulfonation are 2 enzymatic reactions which turn a variety of hydrophobic endogenous and exogenous molecules into water soluble glucuronide and/or sulfate derivatives. These derivatives are easily eliminated from living animals through the bile or urine. The respective enzymes UDP-glucuronosyltransferase and sulfotransferase enzymes are reactive toward various biologically active hormones that control major physiological processes through the intracrine, auto/paracrine or endocrine activation of intracellular nuclear (NRs) or membrane receptors, such as the Liver X-Receptor alpha (LXRa). Preliminary data: Until recently, glucuronidation and sulfonation were thought to play a similar inactivation role for receptor ligands. We recently made the exciting discovery that glucuronidation totally abolishes the ability of 24S-hydroxycholesterol (24SOH-Chol) to activate LXRa, while in contrast sulfonation reinforces its ability to bind to the receptor. These observations provide evidences that sulfonation and glucuronidation exert differential roles in the control of NR-driven gene transcription. Objectives of the program: Because numerous other endo- and exogenous substrates for sulfonation and glucuronidation act as receptor ligands, the overarching aim of our present research program is to further elucidate how deep is the differential impact that the 2 reactions exert on nuclear and membrane receptor ligands activity. Short, mid and long-term objectives are: - Short term (=requested funding period) will evaluate at the molecular level, how sulfonation and glucuronidation impact the intracrine ability of NR ligands to bind to and (in)activate their specific receptor. - Mid- (2026-31) and long term (>10 years) will determine how the autocrine and paracrine (mid) and endocrine (long) activities of nuclear/membrane receptor ligands are differentially affected by the 2 reactions. Experimental design (short term investigations: 2021-2026): We will first perform in vitro experiments to evaluate how sulfonation and glucuronidation affect the ability of selected ligands (such as the polyphenol Resveratrol, the environmental endocrine disruptor Bisphenol A, the anti-estrogen Tamoxifen, as well as the endogenous cholesterol derivatives 24SOH-Chol, CDCA and LCA) to bind to their respective NR (TR-FRET) and exert their agonistic (direct or inverse) or antagonistic activities in relevant cell models. In vivo analyses will then be performed to confirm that events observed in vitro are still occurring in appropriate mice models. Conclusions: by deciphering the differential manner in which sulfonation and glucuronidation interfere with the biological activity of their common substrates, the proposed research program promises a remarkable advance in the fields of cell signalling, metabolism, and will result in a broad range of applications varying from the understanding of signalling termination to potential drug design.