Bile Acids-A Peek Into Their History and Signaling.

Bile acids wear many hats, including those of an emulsifier to facilitate nutrient absorption, a cholesterol metabolite, and a signaling molecule in various tissues modulating itching to metabolism and cellular functions. Bile acids are synthesized in the liver but exhibit wide-ranging effects indicating their ability to mediate organ-organ crosstalk. So, how does a steroid metabolite orchestrate such diverse functions? Despite the inherent chemical similarity, the side chain decorations alter the chemistry and biology of the different bile acid species and their preferences to bind downstream receptors distinctly. Identification of new modifications in bile acids is burgeoning, and some of it is associated with the microbiota within the intestine. Here, we provide a brief overview of the history and the various receptors that mediate bile acid signaling in addition to its crosstalk with the gut microbiota.

Loss of Hepatic Small Heterodimer Partner Elevates Ileal Bile Acids and Alters Cell Cycle-related Genes in Male Mice.

Small heterodimer partner (Shp) regulates several metabolic processes, including bile acid levels, but lacks the conserved DNA binding domain. Phylogenetic analysis revealed conserved genetic evolution of SHP, FXR, CYP7A1, and CYP8B1. Shp, although primarily studied as a downstream target of Farnesoid X Receptor (Fxr), has a distinct hepatic role that is poorly understood. Here, we report that liver-specific Shp knockout (LShpKO) mice have impaired negative feedback of Cyp7a1 and Cyp8b1 on bile acid challenge and demonstrate that a single copy of the Shp gene is sufficient to maintain this response. LShpKO mice also exhibit elevated total bile acid pool with ileal bile acid composition mimicking that of cholic acid-fed control mice. Agonistic activation of Fxr (GW4064) in the LShpKO did not alter the elevated basal expression of Cyp8b1 but lowered Cyp7a1 expression. We found that deletion of Shp led to an enrichment of distinct motifs and pathways associated with circadian rhythm, copper ion transport, and DNA synthesis. We confirmed increased expression of metallothionein genes that can regulate copper levels in the absence of SHP. LShpKO livers also displayed a higher basal proliferation that was exacerbated specifically with bile acid challenge either with cholic acid or 3,5-diethoxycarbonyl-1,4-dihydrocollidine but not with another liver mitogen, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. Overall, our data indicate that hepatic SHP uniquely regulates certain proliferative and metabolic cues.