원문정보
초록
영어
In the onset and progression of ASH and NASH, ceramide is significantly increased by alterations of sphingolipid. However, the regulatory mechanisms by which ceramide drives hepatic steatosis remain poorly understood. Here, we examined the role of ATF3 on ceramide-mediated liver steatosis in ethanol-fed mice or HFD-fed rats. Hepatic steatosis increased in both models are correlated with the increase of ceramide levels in their serum or liver tissues, accompanied with the expression of FAS and SREBP1, which was determined by TNF-α production and TNFR1-dependent pathway. Concomitantly, a stress-inducible ATF3 was significantly increased in these models and it plays as a potent regulator for denovo ceramide synthesis and ceramide-mediated lipid accumulation. Also, ATF3 directly regulates FAS and SREBP1 expression, thereby increases ceramide-mediated lipogenesis and inhibits insulin receptor signaling, which were abolished by ATF3 siRNA. Taken together, our studies suggest that ceramide-mediated ATF3 is a critical regulatory pathway in dynamic regulation of lipid accumulation.