Bile acids (BAs) are evolutionally conserved molecules synthesized in the liver from cholesterol and have been shown to be essential for lipid homeostasis. BAs regulate a variety of metabolic functions via modulating nuclear and membrane receptors. Farnesoid X receptor (FXR) is the most important nuclear receptor for maintaining BA homeostasis. FXR plays a tissue-specific role in suppressing BA synthesis and promoting BA enterohepatic circulation. Disruption of FXR in mice have been implicated in liver diseases commonly occurring in humans, including cholestasis, non-alcoholic fatty liver diseases, and hepatocellular carcinoma. Strategically targeting FXR activity has been rapidly used to develop novel therapies for the prevention and/or treatment of cholestasis and non-alcoholic steatohepatitis. This review provides an updated literature review on BA homeostasis and FXR modulator development.

Bile acids (BAs) are diverse molecules that are synthesized from cholesterol in the liver. The synthesis of BAs has traditionally been shown to occur through two pathways. Cholesterol 7α‐hydroxylase (CYP7A1) performs the initial and rate‐limiting step in the classical pathway, and sterol 27‐hydroxylase (CYP27A1) initiates the hydroxylation of cholesterol in the alternative pathway. While the role of individual BA species as physiological detergents is relatively ubiquitous, their endocrine functions as signaling molecules and roles in disease pathogenesis have been emerging to be BA species–specific. In order to better understand the pharmacologic and toxicologic roles of individual BA species in an in vivo model, we created cholesterol 7α‐hydroxylase (Cyp7a1) and sterol 27‐hydroxylase (Cyp27a1) double knockout (DKO) mice by cross‐breeding single knockout mice (Cyp7a1–/– and Cyp27a1–/–). BA profiling and quantification by liquid chromatography–mass spectrometry of serum, gallbladder, liver, small intestine, and colon of wild‐type, Cyp7a1–/–, Cyp27a1–/–, and DKO mice showed that DKO mice exhibited a reduction of BAs in the plasma (45.9%), liver (60.2%), gallbladder (76.3%), small intestine (88.7%), and colon (93.6%), while maintaining a similar BA pool composition compared to wild‐type mice. The function of the farnesoid X receptor (FXR) in DKO mice was lower, revealed by decreased mRNA expression of well‐known FXR target genes, hepatic small heterodimer partner, and ileal fibroblast growth factor 15. However, response to FXR synthetic ligands was maintained in DKO mice as treatment with GW4064 resulted in similar changes in gene expression in all strains of mice. Conclusion: We provide a useful tool for studying the role of individual BAs in vivo; DKO mice have a significantly reduced BA pool, have a similar BA profile, and maintained response to FXR activation.

Alcoholic fatty liver disease (AFLD) is one of the major causes of liver morbidity and mortality worldwide. We have previously shown that whole-body, but not hepatocyte-specific, deficiency of farnesoid X receptor (FXR) in mice worsens AFLD, suggesting that extra-hepatic FXR deficiency is critical for AFLD development. Intestinal FXR is critical in suppressing hepatic bile acid (BA) synthesis by inducing fibroblast growth factor 15 (FGF15) in mice and FGF19 in humans. We hypothesized that intestinal FXR is critical for reducing AFLD development in mice. To test this hypothesis, we compared the AFLD severity in wild type (WT) and intestine-specific Fxr knockout (FXR Int−/− ) mice following treatment with control or ethanol-containing diet. We found that FXR Int−/− mice were more susceptible to ethanol-induced liver steatosis and inflammation, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: