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Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine

ABSTRACT: The purpose of this study was to elucidate potential effects of fxr mutation on the functional specification of intestinal epithelial cells. To do this, we sorted GFP-positive cells from TgBAC(cldn15la:GFP) transgenics of either fxr+/+ or fxr-/- fish larvae and subjected them to 10X Genomics single-cell RNA-seq. Our results uncovered the requirement of fxr in gene expression and differentiation among multiple intestinal epithelial cell types.

ORGANISM(S): Danio rerio

PROVIDER: GSE173570 | GEO | 2021/04/30

REPOSITORIES: GEO

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Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine

Project description:Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine

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Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.

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