It is well established that chronic and/or excess glucocorticoid (GC) exposure causes glucose and lipid homeostasis disorders. Previous studies have shown that chronic glucocorticoid exposure elevates hepatic ceramide production to inhibit insulin action and increase triglyceride accumulation in the liver. Glucocorticoid treatment not only increases the levels of hepatic ceramides, but also the levels of sphingosine-1-phosphate (S1P). This is because glucocorticoids not only promote the ceramide synthetic pathway, but also increase the expression of sphingosine kinase 1 (Sphk1). Ceramides can be converted to sphingosine, which is further converted to S1P through Sphk1. Here, we reduced the expression of Sphk1 in liver to evaluate its role in chronic glucocorticoid exposure-induced glucose and lipid disorders. We found that mice with reduced hepatic Sphk1 expression had improved glucose and pyruvate tolerance, while no significant difference in insulin tolerance was found upon glucocorticoid treatment. In contrast, glucocorticoid treatment-induced hepatic steatosis and hypertriglyceridemia were exacerbated in these mice with reduced hepatic Sphk1 expression. These results are surprising, as insulin resistance is frequently associated with the development of hepatic dyslipidemia. In this case, while Sphk1 is involved in the insulin resistance induced by glucocorticoids, it plays a negative role in chronic glucocorticoid treatment-induced hepatic dyslipidemia. Here, we will report our recent analysis on the mechanism underlying the role of Sphk1, ceramides, and S1P, in chronic glucocorticoid exposure-induced metabolic disorders.
R.A. Lee: None. A. Tsay: None. M. Chang: None. N. Yiv: None. J.H. Tan: None. J. Wang: None.
National Institutes of Health (R01DK113019)