Transcriptional Control of Trpm6 by the Nuclear Receptor FXR.

Eun Young Kim,Jae Man Lee

doi:10.3390/ijms23041980

Abstract

Farnesoid x receptor (FXR) is a nuclear bile acid receptor that belongs to the nuclear receptor superfamily. It plays an essential role in bile acid biosynthesis, lipid and glucose metabolism, liver regeneration, and vertical sleeve gastrectomy. A loss of the FXR gene or dysregulations of FXR-mediated gene expression are associated with the development of progressive familial intrahepatic cholestasis, tumorigenesis, inflammation, and diabetes mellitus. Magnesium ion (Mg2+) is essential for mammalian physiology. Over 600 enzymes are dependent on Mg2+ for their activity. Here, we show that the Trpm6 gene encoding a Mg2+ channel is a direct FXR target gene in the intestinal epithelial cells of mice. FXR expressed in the intestinal epithelial cells is absolutely required for sustaining a basal expression of intestinal Trpm6 that can be robustly induced by the treatment of GW4064, a synthetic FXR agonist. Analysis of FXR ChIP-seq data revealed that intron regions of Trpm6 contain two prominent FXR binding peaks. Among them, the proximal peak from the transcription start site contains a functional inverted repeat 1 (IR1) response element that directly binds to the FXR-RXRα heterodimer. Based on these results, we proposed that an intestinal FXR-TRPM6 axis may link a bile acid signaling to Mg2+ homeostasis.

Highlights

Sci. 2022, 23, 1980. https://doi.org/Farnesoid x receptor (FXR) is a member of the nuclear receptor superfamily and is primarily expressed in liver, intestine, and kidney
We found that a deletion construct of DR1 (+42,865 to +43,185) exhibited about 60% of maximal luciferase activity shown in fulllength of Trpm6 PP-Luc construct upon co-treatments of both agonists
The cold mutant competitors of the IR1a oligonucleotide sequences (Trpm6 mutant IR1a) were almost unable to compete for binding at a 1, 100, or 1000-fold molar excess. These results demonstrated that the FXR-RXRα heterodimer could bind to the IR1a located between nucleotides +42,936 and +42,948 in the Trpm6 gene (Figure 6e)

Summary

Introduction

Sci. 2022, 23, 1980. https://doi.org/FXR ( known as NR1H4 and RIP14) is a member of the nuclear receptor superfamily and is primarily expressed in liver, intestine, and kidney. Because of the identifications of some bile acids as endogenous agonist or antagonist ligands, FXR has been considered as an adopted orphan nuclear receptor [1,2,3,4,5,6,7,8]. As a bile acid sensor in the fed state, FXR in the intestine and liver is suspected to be activated by enterohepatic circulation along with fat-soluble nutrients and vitamins. This concept allowed us to demonstrate that postprandial activation of FXR is necessary for suppressing autophagy, an intracellular degradation process involved in lysosomes [26,27].

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