Inhibition of Rac1 by chemical inhibitor (553502, Calbiochem) or gene silencing by shRNA not only decreased phagocytosis of dying hepatocytes by the LX2 cells but also prevented their activation following phagocytosis of the dying hepatocytes. CONCLUSION: Rac1 signaling plays an important role in pahgocytosis of the necrotic dying hepatocytes by the HSCs. Internalization

of the necrotic hepatocytes by HSCs induce their activation and fibrogenesis. Disclosures: The following people have nothing to disclose: LDK378 mouse Suman Santra, Abhijit Chowdhury, Debasree Bishnu, Gopal K. Dhali, Amal Santra Prolonged exposure to alcohol, a hepatotoxicant, causes liver fibrosis in a subset of patients. The mechanisms by which alcohol exerts its profibrotic function are incompletely understood. After hepatotoxicant exposure, the liver is injured but will repair itself, in part, through hepatocyte proliferation. If uninjured hepatocytes do not quickly enter the cell cycle, they are susceptible to additional injury and/or death which could enhance fibrotic signaling in the liver. Therefore, here, we tested the hypothesis that liver regeneration after carbon tetrachloride (CCl4)-induced liver injury is impaired by moderate (2% check details v/v) ethanol and is associated with enhanced profibrotic signatures in liver. After 4 days on ethanol-containing or control liquid diets, wild-type mice were injected with one dose

of CCl4, intraperitoneally. Mice were euthanized 24, 48, 72 and 96h after CCl4 exposure. Plasma alanine aminotransferase, hepatic Cyp2E1 activity and hepatic triglyceride levels were not different between pair- and ethanol-fed animals. Hepatic transcripts for Col1A1, Hsp47 and aSMA, intermediate biomarkers of fibrosis, were increased 72h after CCl4 in both pair and ethanol-fed mice; this increase was ∼2-fold

greater after ethanol feeding. The G1/S-phase cyclin, E1 was reduced 24h, while the G2 and G2/M cyclins, A2 and B1, respectively, were reduced 48h after CC^ exposure in ethanol-fed mice compared to pair-fed mice. In parallel, TNFα, a cytokine important for cell cycle induction, was reduced in ethanol-fed mice 24h after CCl4; this reduction was not due to reduced numbers of F4/80-postive macrophages. 上海皓元 Peak cyclin A2 and B1 were delayed from 48h after CC^ in pair-fed mice to 72h after CCl4 in ethanol-fed mice. Consistently, phosphorylation of retinoblastoma (Rb), a protein involved in early G2/M phase transition of the cell cycle, was increased at 72h in ethanol-fed mice relative to pair-fed mice. Finally, hepatic mitotic figures were increased 3-fold after ethanol feeding 72h post CCl4 exposure. Taken together, moderate ethanol is associated with reduced TNFα production, delayed liver regeneration and increased profibrotic changes in liver after CCl4 exposure. These studies were supported by grants to M.T.P. (P20 GM103549, R00 AA017918). Disclosures: The following people have nothing to disclose: Krutika T.