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Review
. 2018 Jul 16;19(7):2069.
doi: 10.3390/ijms19072069.

Update on FXR Biology: Promising Therapeutic Target?

Chang Yeob Han  1
Affiliations
Review

Update on FXR Biology: Promising Therapeutic Target?

Chang Yeob Han. Int J Mol Sci. .

Abstract

Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metabolism, and contributes to inter-organ communication, in particular the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19). The metabolic effects of FXR are also involved in gut microbiota. In addition, FXR has various functions in the kidney, adipose tissue, pancreas, cardiovascular system, and tumorigenesis. Consequently, the deregulation of FXR may lead to abnormalities of specific organs and metabolic dysfunction, allowing the protein as an attractive therapeutic target for the management of liver and/or metabolic diseases. Indeed, many FXR agonists have been being developed and are under pre-clinical and clinical investigations. Although obeticholic acid (OCA) is one of the promising candidates, significant safety issues have remained. The effects of FXR modulation might be multifaceted according to tissue specificity, disease type, and/or energy status, suggesting the careful use of FXR agonists. This review summarizes the current knowledge of systemic FXR biology in various organs and the gut⁻liver axis, particularly regarding the recent advancement in these fields, and also provides pharmacological aspects of FXR modulation for rational therapeutic strategies and novel drug development.

Keywords: FXR (farnesoid X receptor); liver diseases; metabolic disorders; nuclear receptor; pharmacological application.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Systemic effects of farnesoid X receptor (FXR) activation. FXR contributes to maintenance of homeostasis and the integrity of various organs, including the liver. The arrows present the effects of FXR agonism on the pathophysiology of the organs (Note: *1—the effects of FXR on non-obstructive and obstructive cholestasis are different; *2—the roles of tissue-specific FXR in metabolic disorders are varying according to conditions). ALD—alcoholic liver disease; DILI—drug-induced liver injury; GSIS—glucose-stimulated insulin secretion; HCC—hepatocellular carcinoma; I/R—ischemia-reperfusion; NAFLD—nonalcoholic fatty liver disease; NASH—nonalcoholic steatohepatitis; NSCLC—non-small cell lung cancer.
Figure 2
Figure 2
The roles of FXR in the gut–liver axis. FXR contributes to the crosstalk between liver and intestine through the regulation of hepatic bile acids (BAs) synthesis and intestinal fibroblast growth factor-15/19 (FGF-15/19) secretion. FGF15/19 controls the BA production via hepatic FGF receptor 4 (FGFR4) signaling. BAs act on TGR5 as well as FXR, contributing to metabolic homeostasis. Intestinal microbiota affects the composition of BAs, leading to changes in FXR activities. Dotted gray arrows represent the transport of BAs or FGF15/19 through the bile duct or the portal vein, respectively. Dotted black arrows indicate the activating effects, whereas dotted T bar arrows indicate the inhibitory effects. Solid blue arrow represents the effects of gut microbiota on the composition of BAs, while red arrows represent the inter-organ crosstalk between liver and intestine.
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