The Role of Sphingosine 1 Phosphate Receptor 2 Signaling in Chronic Glucocorticoid Exposure Induced Hepatic Steatosis and Hypertriglyceridemia

Glucocorticoids (GC) are potent anti-inflammatory agents that are frequently used to treat inflammatory diseases. Chronic glucocorticoid treatment, however, causes unwanted adverse effects such as hypertriglyceridemia and hepatic steatosis. Hepatic sphingosine-1-phosphate receptor 2 knockdown in mice reduced chronic GC treatment induced triglyceride accumulation in the liver and plasma. Chronic glucocorticoid treatment increased the recruitment of sterol regulatory element-binding protein 1c (Srebp1c) to the sterol regulatory element of mouse fatty acid synthase (Fasn) gene. This response was attenuated in hepatic S1PR2 knockdown mice. Chronic glucocorticoid treatment also increased the recruitment of carbohydrate response element binding protein (ChREBP) to the carbohydrate response elements (ChOREs) of lipogenic and glycolytic genes such as pyruvate kinase L/R (Pklr) and malic enzyme 1 (Me1) in mice liver. This response was also reduced in hepatic S1PR2 knockdown mice. Reducing hepatic ChREBP expression reduced the expression of Pklr, Me1 and Fasn. However, long-term glucocorticoid induced triglyceride accumulation in the liver and the plasma were not affected whereas the hepatic lactate levels were decreased. Thus, ChREBP plays a major role in chronic glucocorticoid induced glycolysis whereas its role in hypertriglyceridemia and hepatic steatosis was modest. Overall, this study demonstrated that hepatic S1PR2 signaling is involved in chronic glucocorticoid exposure activated Srebp1c and ChREBP, which promote lipogenesis and glycolysis, respectively. Overall design: To establish the role of S1PR2 in chronic Dexamethasone (a synthetic glucocorticoid) treatment, we used AAV8 to knockdown S1PR2 in a liver-specific manner. We performed RNA sequencing in mouse liver to identify differentially expressed genes between control and S1PR2 knockdown mice treated with or without Dexamethasone