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Targeting FXR in Cholestasis

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Bile Acids and Their Receptors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 256))

Abstract

The farnesoid X receptor (FXR, NR1H4) is a bile acid (BA)-activated transcription factor, which is essential for BA homeostasis. FXR and its hepatic and intestinal target genes, small heterodimer partner (SHP, NR0B2) and fibroblast growth factor 15/19 (Fgf15 in mice, FGF19 in humans), transcriptionally regulate BA synthesis, detoxification, secretion, and absorption in the enterohepatic circulation. Furthermore, FXR modulates a large variety of physiological processes, such as lipid and glucose homeostasis as well as the inflammatory response. Targeted deletion of FXR renders mice highly susceptible to cholic acid feeding resulting in cholestatic liver injury, weight loss, and increased mortality. Combined deletion of FXR and SHP spontaneously triggers early-onset intrahepatic cholestasis in mice resembling human progressive familial intrahepatic cholestasis (PFIC). Reduced expression levels and activity of FXR have been reported in human cholestatic conditions, such as PFIC type 1 and intrahepatic cholestasis of pregnancy. Recently, two pairs of siblings with homozygous FXR truncation or deletion variants were identified. All four children suffered from severe, early-onset PFIC and liver failure leading to death or need for liver transplantation before the age of 2. These findings underscore the central role of FXR as regulator of systemic and hepatic BA levels. Therefore, targeting FXR has been exploited in different animal models of both intrahepatic and obstructive cholestasis, and the first FXR agonist obeticholic acid (OCA) has been approved for the treatment of primary biliary cholangitis (PBC). Further FXR agonists as well as a FGF19 analogue are currently tested in clinical trials for different cholestatic liver diseases. This chapter will summarize the current knowledge on the role of FXR in cholestasis both in rodent models and in human diseases.

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Acknowledgment

Our own studies are supported by DFG through SFB974 “Communication and systems relevance in liver damage and regeneration.”

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  1. Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Düsseldorf, Germany

    Verena Keitel, Carola Dröge & Dieter Häussinger

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  1. Verena Keitel
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  2. Carola Dröge
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  3. Dieter Häussinger
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Correspondence to Verena Keitel .

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  1. University of Perugia, School of Medicine, Perugia, Italy

    Stefano Fiorucci

  2. S.C. Gastroenterologia, Azienda Ospedaliera di Perugia, Perugia, Italy

    Eleonora Distrutti

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Keitel, V., Dröge, C., Häussinger, D. (2019). Targeting FXR in Cholestasis. In: Fiorucci, S., Distrutti, E. (eds) Bile Acids and Their Receptors. Handbook of Experimental Pharmacology, vol 256. Springer, Cham. https://doi.org/10.1007/164_2019_231

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