Project Summary Non-alcoholic fatty liver disease (NAFLD), the most common of liver pathologies, is one of the most profound health disparities. The molecular pathway(s) associated with the pathogenesis of NAFLD and its subsequent progression to nonalcoholic steatohepatitis (NASH) remains elusive. We have previously shown that Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) plays a critical role in insulin clearance in the liver and links hyperinsulinemia to NAFLD/NASH. Preliminary data identify that Cell death-Inducing DFF45-like Effector (Cidec;; also termed Fsp27), a lipid droplet associated protein that regulates lipolysis in the adipose tissue, regulates liver metabolic function and fibrosis via hepatic CEACAM1. Most interestingly, we found that FSP27–/– mice exhibited lower hepatic CEACAM1 levels on regular and HF diets, and subsequently, impaired insulin clearance and hyperinsulinemia that could in turn, mediate hepatic insulin resistance. In addition to hyperinsulinemia-driven hepatic steatosis, Fsp27–/– mice also exhibited elevated plasma Endothelin 1 and spontaneous hepatic bridging-fibrosis, comparable to the phenotype of Ceacam1 knockout mice. To study the gain-of-function we have developed an innovative adipose-specific transgenic mouse model expressing human- FSP27. Our preliminary data show that this mouse model exhibits normal insulin and glucose tolerance in response to HF intake in parallel to a remarkable ~5-fold induction of hepatic CEACAM1 protein levels. Since lipolysis-derived fatty acids from white adipose tissue (WAT) reduces hepatic CEACAM1 expression and forced liver-specific overexpression of CEACAM1 or its adenoviral-mediated delivery protects against HF diet-induced insulin resistance and steatohepatitis, and fibrosis in WAT and liver, we hypothesize that reduction of FSP27 in adipocytes causes FFA release and redistribution to the liver to reduce hepatic CEACAM1 levels and subsequently, cause hepatocyte injury and hepatic fibrosis. We postulate the underlying mechanisms to involve activation of epidermal growth factor receptor by fatty acids and Endothelin 1, the expression of which is upregulated by the MEK/ERK-PPARg pathway. Aim 1 will investigate whether CEACAM1 in hepatocytes regulates hepatic fibrosis in mice with adipocyte-specific deletion of Fsp27 (paracrine regulation). Aim 2 will examine the cell-autonomous fibrogenic effect of FSP27 deletion in hepatic stellate cells. This approach is well- thought and well-designed where novel mouse models (both knockout and transgenic) will be used to study the cross- talk between adipose tissue and liver which plays a critical role in the development of hepatic fibrosis via altering FSP27. A strength of this proposal is an inter...