Bile Acids and FXR: Novel Targets for Liver Diseases

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Abstract

Bile acids (BAs) are evolutionally conserved molecules synthesized in the liver from cholesterol and have been shown to be essential for lipid homeostasis. BAs regulate a variety of metabolic functions via modulating nuclear and membrane receptors. Farnesoid X receptor (FXR) is the most important nuclear receptor for maintaining BA homeostasis. FXR plays a tissue-specific role in suppressing BA synthesis and promoting BA enterohepatic circulation. Disruption of FXR in mice have been implicated in liver diseases commonly occurring in humans, including cholestasis, non-alcoholic fatty liver diseases, and hepatocellular carcinoma. Strategically targeting FXR activity has been rapidly used to develop novel therapies for the prevention and/or treatment of cholestasis and non-alcoholic steatohepatitis. This review provides an updated literature review on BA homeostasis and FXR modulator development.

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Identification of a nuclear receptor for bile acids.

M. Makishima, A. Okamoto, J Repa … (1999)

Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter. These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport.

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A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.

Bryan Goodwin, Stacey A. Jones, Roger R. Price … (2000)

Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.

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Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.

H. Wang, J. Chen, K Hollister … (1999)

The major metabolic pathway for elimination of cholesterol is via conversion to bile acids. In addition to this metabolic function, bile acids also act as signaling molecules that negatively regulate their own biosynthesis. However, the precise nature of this signaling pathway has been elusive. We have isolated an endogenous biliary component (chenodeoxycholic acid) that selectively activates the orphan nuclear receptor, FXR. Structure-activity analysis defined a subset of related bile acid ligands that activate FXR and promote coactivator recruitment. Finally, we show that ligand-occupied FXR inhibits transactivation from the oxysterol receptor LXR alpha, a positive regulator of cholesterol degradation. We suggest that FXR (BAR) is the endogenous bile acid sensor and thus an important regulator of cholesterol homeostasis.

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Contributors

Mary Stofan: URI : http://loop.frontiersin.org/people/1072483/overview

Grace L. Guo: URI : http://loop.frontiersin.org/people/503387/overview

Journal

Journal ID (nlm-ta): Front Med (Lausanne)

Journal ID (iso-abbrev): Front Med (Lausanne)

Journal ID (publisher-id): Front. Med.

Title: Frontiers in Medicine

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2296-858X

Publication date (Electronic): 11 September 2020

Publication date Collection: 2020

Volume: 7

Electronic Location Identifier: 544

Affiliations

[1] ¹Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University , Piscataway, NJ, United States

[2] ²Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey , Piscataway, NJ, United States

[3] ³VA New Jersey Health Care System, Veterans Administration Medical Center , East Orange, NJ, United States

Author notes

Edited by: Shannon Glaser, Texas A&M University College of Medicine, United States

Reviewed by: Roberto Gramignoli, Karolinska Institutet (KI), Sweden; Lindsey Kennedy, Indiana University Bloomington, United States

*Correspondence: Grace L. Guo guo@ 123456eohsi.rutgers.edu

This article was submitted to Gastroenterology, a section of the journal Frontiers in Medicine

Article

DOI: 10.3389/fmed.2020.00544

PMC ID: 7516013

PubMed ID: 33015098

SO-VID: 9492c75c-455f-4002-9fae-d3432c3fc40d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 12 May 2020

Date accepted : 30 July 2020

Page count

Figures: 2, Tables: 0, Equations: 0, References: 124, Pages: 12, Words: 10710

Funding

Funded by: National Institutes of Health 10.13039/100000002

Funded by: U.S. Department of Veterans Affairs 10.13039/100000738

Funded by: Rutgers, The State University of New Jersey 10.13039/100011132

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Bile Acids and FXR: Novel Targets for Liver Diseases

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Most cited references 96

Identification of a nuclear receptor for bile acids.

A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.

Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.

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