Update on FXR Biology: Promising Therapeutic Target?

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.

Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease

“…Bile acids are steroid‐derived molecules synthesized in the liver and secreted into the intestinal lumen that facilitate lipid absorption and additionally regulate metabolism by activation of a number of host receptors, including farnesoid X receptor (FXR) and the membrane‐associated G protein‐coupled receptor (TGR5) . Distinct bile acids have varying affinities for host receptors and may act either as receptor agonists or antagonists, with subsequent effects on the regulation of basal metabolism and energy expenditure, lipid metabolism, nitric oxide synthesis, intestinal motility and permeability, and immune response …”

“…(115) Distinct bile acids have varying affinities for host receptors and may act either as receptor agonists or antagonists, with subsequent effects on the regulation of basal metabolism and energy expenditure, lipid metabolism, nitric oxide synthesis, intestinal motility and permeability, and immune response. (116,117) In addition to their effects on the host, bile acids prevent intestinal bacterial overgrowth, both directly through membrane-damaging effects and indirectly through induction of antimicrobial protein expression; thus, they also play an important role in shaping gut microbiome membership. (118) Indeed, microbial bile acid resistance offers a fitness advantage in the gut and is commonly complemented by the capacity to deconjugate bile acids and convert primary bile acids to secondary bile acids.…”

Synthetic Maturation of Multilineage Human Liver Organoids via Genetically Guided Engineering

“…FXR agonists are being tested in clinical trials for controlling liver inflammation, non-alcoholic fatty liver disease, and fibrosis (Han, 2018). Since DesLO contains a population of SLCs, we asked whether SLCs can sense and respond to fibrotic and FXR-mediated antifibrotic stimuli.…”

Mechanisms Underlying Bone Loss Associated with Gut Inflammation

“…The farnesoid X receptor (FXR), a nuclear receptor for bile acids, is highly expressed in intestine and liver and responsible for maintaining bile acid homeostasis. FXR displays various functions in different organs, and the FXR antagonists have been developed for pre-clinical and clinical application for management of liver and other metabolic disease [121]. FXR−/− mice display compromised intestinal epithelial barrier due to increased bacterial invasion [122], increased colon cell proliferation and apoptotic goblet cells, accompanied with upregulation of genes involved in cell cycle progression and inflammation, such as cyclin D1 and IL-6 [83].…”