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      Farnesoid X receptor (FXR): Structures and ligands

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          Abstract

          Farnesoid X receptor (FXR) is a bile acid activated nuclear receptor (BAR) and is mainly expressed in the liver and intestine. Upon ligand binding, FXR regulates key genes involved in the metabolic process of bile acid synthesis, transport and reabsorption and is also involved in the metabolism of carbohydrates and lipids. Because of its important functions, FXR is considered as a promising drug target for the therapy of bile acid-related liver diseases. With the approval of obeticholic acid (OCA) as the first small molecule to target FXR, many other small molecules are being evaluated in clinical trials. This review summarizes the structures of FXR, especially its ligand binding domain, and the development of small molecules (including agonists and antagonists) targeting FXR.

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          Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.

          Sama SAYIN, Annika Wahlström, Jenny Felin … (2013)
          Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

            Zobair Younossi, Vlad Ratziu, Rohit Loomba … (2020)
            Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.
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              Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.

              Brent Neuschwander-Tetri, Rohit Loomba, Arun Sanyal … (2015)
              The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.
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                Author and article information

                Contributors
                Hudie Wei
                Yongheng Chen
                Journal
                Journal ID (nlm-ta): Comput Struct Biotechnol J
                Journal ID (iso-abbrev): Comput Struct Biotechnol J
                Title: Computational and Structural Biotechnology Journal
                Publisher: Research Network of Computational and Structural Biotechnology
                ISSN (Electronic): 2001-0370
                Publication date PMC-release: 20 April 2021
                Publication date Collection: 2021
                Publication date (Electronic): 20 April 2021
                Volume: 19
                Pages: 2148-2159
                Affiliations
                [a ]Department of Pathology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
                [b ]Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
                Author notes
                [* ]Corresponding authors at: Department of Pathology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. hudiewei18@ 123456163.com yonghenc@ 123456163.com
                Article
                Publisher Item ID: S2001-0370(21)00141-0
                DOI: 10.1016/j.csbj.2021.04.029
                PMC ID: 8091178
                PubMed ID: 33995909
                SO-VID: a905c5dd-c39b-4565-9f2d-c7bbbe58340f
                Copyright © © 2021 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 10 December 2020
                Date revision received : 10 April 2021
                Date accepted : 10 April 2021
                Categories
                Subject: Review

                Keywords: farnesoid x receptor,structure,ligand binding domain,agonists,antagonists
                Data availability:
                Keywords: farnesoid x receptor, structure, ligand binding domain, agonists, antagonists

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