Effect of FTY720P on lipid accumulation in HEPG2 cells

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic lipid accumulation due to impaired lipid metabolism. Although a correlation was found between NAFLD and sphingosine-1-phosphate (S1P), the role of the sphingolipid remains controversial. The aim of this study was to investigate any involvement of S1P in steatosis using its analog FTY720P and HepG2 cells. Lipid accumulation was induced by incubating the cells in a mixture of oleic and palmitic acid, and was quantified using Oil Red O. The involvement of signaling mediators was studied using pharmacological inhibitors and western blot analysis. FTY720P increased lipid accumulation, but this increase wasn’t maintained in the presence of inhibitors of S1PR3, Gq, SREBP, mTOR, PI3K, and PPARγ indicating their involvement in the process. The results revealed that FTY720P binds to S1PR3 which activates sequentially Gq, PI3K, and mTOR leading to an increase in SREBP expression and PPARγ activation. It was concluded that in presence of a high level of fatty acids, lipid accumulation is increased in hepatocytes by the exogenously added FTY720P.

Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis

“…This drug acts as an S1P antagonist, downregulating CerS2 ( 106 , 107 ), thereby suggesting a mechanism of reduced very-long-chain ceramides. Mechanistically, fingolimod also binds to S1PR3, increasing SREBP expression and activating PPARγ through the activation of Gq, PI3K, and mTOR ( 87 ). In mice fed obesogenic diets, the administration of fingolimod has been associated with reduced steatosis, liver injury, and inflammation ( 85 ).…”