Farnesoid X Receptor Agonists as Therapeutic Target for Cardiometabolic Diseases

Abstract

Cardiometabolic diseases are characterized as a combination of multiple risk factors for cardiovascular disease (CVD) and metabolic diseases including diabetes mellitus and dyslipidemia. Cardiometabolic diseases are closely associated with cell glucose and lipid metabolism, inflammatory response and mitochondrial function. Farnesoid X Receptor (FXR), a metabolic nuclear receptor, are found to be activated by primary BAs such as chenodeoxycholic acid (CDCA), cholic acid (CA) and synthetic agonists such as obeticholic acid (OCA). FXR plays crucial roles in regulating cholesterol homeostasis, lipid metabolism, glucose metabolism, and intestinal microorganism. Recently, emerging evidence suggests that FXR agonists are functional for metabolic syndrome and cardiovascular diseases and are considered as a potential therapeutic agent. This review will discuss the pathological mechanism of cardiometabolic disease and reviews the potential mechanisms of FXR agonists in the treatment of cardiometabolic disease.

Farnesoid X receptor (FXR): Structures and ligands

“…In fact, some groups aimed at the unexplored field of FXR antagonists ( Fig. 5 ) [62] , [65] , [85] , [86] . FXR antagonists have proven beneficial in animal models of cholestasis and hypercholesterolemia, as well as in pancreatic and colon cancers [87] , [88] , [89] .…”

Tris(1,3-dichloro-2-propyl) phosphate is a metabolism-disrupting chemical in male mice

“…FXR was activated by TDCPP in vitro, but we did not find transcriptional evidence of FXR activation in mouse livers. As FXR activation is generally protective against impaired glucose tolerance ( Gonzalez-Regueiro et al, 2017 ; Li et al, 2020 ; Shapiro et al, 2018 ), it was not expected that FXR-regulated genes would be differentially expressed in TDCPP-exposed livers, especially in insulin resistant males. The xenobiotic nuclear receptor, PXR, was activated most robustly, and this was confirmed by gene expression analysis is livers of both male and female mice exposed to TDCPP.…”

Intestinal Barrier in Human Health and Disease

“…Indeed, liver disease is associated with impaired BA metabolism, in particular a lower fecal BA concentration due to decreased synthesis, and a reduced primary to secondary bile acid conversion due to dysbiosis [ 159 , 160 ]. BAs interact with the farnesoid x receptor (FXR), a nuclear receptor present in the liver as well as in the gut, involved in the regulation of BA synthesis, glucose and lipid metabolism, and inflammatory response [ 161 , 162 , 163 , 164 ]. The modification of the BA pool in cirrhotic patients and the consequent dysfunction of FXR lead to a pro-inflammatory response [ 146 ].…”