Nuclear receptor farnesoid X receptor activation inhibits fatty acid synthesis through the liver X receptor-α-sterol regulatory element binding protein-1c pathway universally in animals, but also has human-specific crosstalk with the peroxisome proliferator-activated receptor-α. 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-α-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-α and fatty acid β-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.
Keywords: bile acids; fatty liver; human-specific crosstalk; lipolysis; nuclear receptor ligand.