Human-specific dual regulations of FXR-activation for reduction of fatty liver using in vitro cell culture model.

ABSTRACT: Nuclear receptor farnesoid X receptor activation inhibits fatty acid synthesis through the liver X receptor-?-sterol regulatory element binding protein-1c pathway universally in animals, but also has human-specific crosstalk with the peroxisome proliferator-activated receptor-?. The effects of farnesoid X receptor-ligands on both the synthesis and degradation of fatty liver through nuclear receptor-related regulation were investigated in both human and murine hepatocytes. A fatty liver culture cell model was established using a synthetic liver X receptor-?-ligand (To901317) for both human and mouse non-neoplastic hepatocytes. The hepatocytes were exposed to natural or synthetic farnesoid X receptor-ligands (bile acids, GW4064, obeticholic acid) together with or after To901317. Cellular triglyceride accumulation was significantly inhibited by the farnesoid X receptor-ligands along with inhibition of lipogenic genes and up-regulation of farnesoid X receptor-target small heterodimer partner in both human and mouse cells. The accumulated triglyceride was significantly degraded by the farnesoid X receptor-ligands only in the human cells accompanied with the up-regulations of peroxisome proliferator-activated receptor-? and fatty acid ?-oxidation. Farnesoid X receptor-ligands can be therapeutic agents for treating human fatty liver through dual effects on inhibition of lipogenesis and on enhancement of lipolysis.

SUBMITTER: Miyazaki T 

PROVIDER: S-EPMC6436045 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature