Thus, bile acids themselves tightly regulate bile acid homeostasis in biosynthesis from cholesterol, excretion into bile, and in the enterohepatic circulation through a negative feedback mechanism involving FXR activation. In addition to bile acid Selleck DAPT homeostasis, FXR is associated

with various metabolic pathways, especially in lipid metabolism; therefore, synthetic FXR ligands have been developed as drugs for treatment of lipid metabolism-related diseases.[2] Most of the bile acids in the liver are conjugated with taurine or glycine to increase their polarity, which results in increased excretion into the bile and reduced toxicity. Taurine- or glycine-conjugated bile acids also more efficiently promote absorption of lipids in the intestine compared to unconjugated bile acids. Bile acid–amino acid conjugation involves two sequential enzyme reactions mediated by adenosine triphosphate-dependent microsomal bile acid coenzyme

A (CoA) synthetase (BACS), which converts a bile acid to an Alpelisib price acyl-CoA thioester; and bile acid-CoA : amino acid N-acetyltransferase (BAT), which transfers the acyl-CoA thioester to taurine or glycine. Pircher et al. showed that both BACS and BAT genes are regulated by FXR via inverted repeat-1 elements cognate to the FXR/retinoid X receptor heterodimer in human and rat liver, which implies that bile acids themselves also regulate bile acid–amino acid conjugation.[3] In this issue of Hepatology Research, Kerr et al. describe the influence of FXR activation on the properties of taurine biosynthesis and conjugation of bile acids with taurine in mouse liver, using p.o. administration of a bile acid (cholic acid) or a bile acid sequestrant (cholestyramine). SHP mRNA expression was significantly increased by www.selleck.co.jp/products/AG-014699.html a cholic acid diet and significantly decreased by cholestyramine, while CYP7A1 mRNA expression showed the opposite changes. The level of mRNA for cysteine sulfinic acid decarboxylase (CSAD), a key enzyme in hepatic taurine biosynthesis from cysteine, was significantly decreased by cholic acid and significantly increased by cholestyramine.

CSAD mRNA levels in the liver were also significantly decreased in mice treated with a synthetic FXR ligand (GW4064) and significantly increased in SHP–/– mice. These findings imply that FXR activation downregulates taurine biosynthesis. In regulation of bile acid–amino acid conjugation, BAT mRNA was significantly decreased or unchanged in GW4064-treated and SHP–/– mice, and BACS mRNA was unchanged in both types of mice. Indeed, Pircher et al. suggested that FXR-dependent induction of BACS and BAT mRNA may occur in rats, but not in mice, and that regulation of both genes by FXR may also occur in humans.[3] Thus, there are species differences in regulation of taurine biosynthesis and bile acid-amino acid conjugation by FXR activation among mice, rats and humans, and further studies in human subjects are required.