Regulation of bile acid receptor activity ☆

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Abstract

Many receptors can be activated by bile acids (BAs) and their derivatives. These include nuclear receptors farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR), as well as membrane receptors Takeda G protein receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cholinergic receptor muscarinic 2 (CHRM2). All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure. Because epigenetic regulation is critical for organisms to adapt to constant environmental changes, this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid receptors. In addition, the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs. Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.

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Most cited references 70

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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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The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.

J L Staudinger, B. Goodwin, S Jones … (2001)

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16alpha-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7alpha-hydroxylase (Cyp7a1) and the Na(+)-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

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Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism.

Preeti Pathak, Cen Xie, Robert Nichols … (2018)

Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the FEX-induced metabolic phenotypes and inhibited taurolithocholic acid synthesis, adipose tissue browning, and liver bile acid synthesis gene expression but further increased intestinal FXR target gene expression. FEX treatment effectively improved lipid profiles, increased GLP-1 secretion, improved glucose and insulin tolerance, and promoted adipose tissue browning, while antibiotic treatment reversed the beneficial metabolic effects of FEX in obese and diabetic mice.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101705555

Journal ID (pubmed-jr-id): 46534

Journal ID (nlm-ta): Liver Res

Journal ID (iso-abbrev): Liver Res

Title: Liver research

ISSN (Print): 2096-2878

ISSN (Electronic): 2542-5684

Publication date Nihms-submitted: 24 May 2019

Publication date (Electronic): 23 September 2018

Publication date (Print): December 2018

Publication date PMC-release: 10 April 2020

Volume: 2

Issue: 4

Pages: 180-185

Affiliations

Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA

Author notes

Authors’ contributions

Y.-J.Y. Wan and L. S wrote the manuscript and approved the final version of the manuscript.

[☆]

Edited by Peiling Zhu and Genshu Wang.

[* ]Corresponding author. yjywan@ 123456ucdavis.edu (Y.-J.Y. Wan).

Article

Manuscript ID: NIHMS1031413

DOI: 10.1016/j.livres.2018.09.008

PMC ID: 7147511

PubMed ID: 32280557

SO-VID: 50c521ac-edca-4cd3-9599-c6554446e4ff

License:

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

Regulation of bile acid receptor activity ^☆

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Most cited references 70

Identification of a nuclear receptor for bile acids.

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.

Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism.

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