Transcriptional Control of Trpm6 by the Nuclear Receptor FXR

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-RXR alpha heterodimer. Based on these results, we proposed that an intestinal FXR-TRPM6 axis may link a bile acid signaling to Mg2+ homeostasis.

Automated summary

The FXR receptor is essential for liver function, bile acid synthesis, glucose metabolism, and enzyme activity. Research shows that FXR in intestinal epithelial cells is directly linked to the Mg2+ channel Trpm6, potentially connecting bile acid signaling to Mg2+ homeostasis.