Role of Ceramide in Hepatic Stellate Cell Activation and Liver Fibrosis
Location(s): United States
In prior work, we have developed a small molecule screen to identify compounds that inactivate hepatic stellate cells (HSCs), the primary cell type responsible for hepatic fibrosis. Through analysis of a hit, we identified that the sphingolipid ceramide can profoundly inhibit the activated effector phenotype of HSCs. Our work has identified a potential antifibrotic role for inhibition of acid ceramidase (aCDase), the enzyme responsible for ceramide metabolism. In this proposal, the we seek to elucidate the mechanism by which ceramide accumulation inactivates HSCs and define the role of aCDase in fibrosis progression. The specific goals of the study are to: 1) determine how ceramide mediates HSC inactivation; and 2) define the impact of aCDase depletion and inhibition on fibrosis development in vivo.