315 FoxO3 REGULATES HEPATIC GLUCOSE PRODUCTION

regeneration is insufficient. We here further investigated the expression pattern of the novel oval cell marker Neighbor of Punc E 11 (Nope) in liver regeneration after chronic (Mdr2−/− mice) and/or acute liver injury (partial hepatectomy) in adult mice. Methods: For analysis of chronic liver injury, liver tissue was extracted from Mdr2−/− of different age and stage of fibrosis. Additionally, Mdr2−/− and Balb/c mice were analyzed for the impact of acute liver injury with or without pretreatment with DNAalkylating reagents to block hepatocytic proliferation. 24 hours to 6 months postoperatively, mice were sacrificed and the liver tissue was tested for expression levels of Nope via quantitative RT-PCR. Costainings were performed for Nope in combination with epithelial-specific marker E-cadherin, the biliary marker CK19 and markers of hepatic stem/progenitor cells (A6, EpCAM). Results: While normal adult liver tissue shows only negligible expression of Nope, chronic liver injury in Mdr2−/− mice leads to a considerably increased expression level of Nope. Co-stainings with CK19 demonstrated a bile-duct-specific expression of Nope in these mice. While partial hepatectomy in the normal adult liver has no effect on Nope, it leads to the development of Nope-positive hepatocytic cell clusters in the chronically injured Mdr2−/− mouse model especially if hepatocyte proliferation is blocked. These Nope-positive clusters are negative for CK19 but stain positive for E-cadherin. Oval cell markers A6 and EpCAM both show coexpression with Nope in proliferating ductular cells, but only a minor hepatocytic cell fraction within Nope-positive clusters also stains positive for A6. Conclusion: We here report the expression of the novel oval cell marker Nope in liver regeneration after chronic and/or acute liver injury. The increase of Nope in chronic liver injury is mainly limited to bile ducts, but especially after additional acute liver injury and blocked hepatocytic regeneration a small population of Nopepositive hepatocytic progenitor cells arises. We conclude that Nope detects a novel progenitor cell population within the regenerating adult liver.