Milk fat globule-EGF factor 8 and hepatocyte apoptosis-induced liver wound healing response

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Liver injury-associated diseases remain a major public health problem in the U.S. and VA healthcare system. Evidence shows that liver injury can persist if either etiologic agents are not removed or healing is disrupted. Impaired resolving severe acute liver injury can lead to critical illness conditions, liver failure and death. Patients with persistent liver injury display chronic liver disease which can progress to cirrhosis and liver carcinoma. Thus, it is critical to advance our knowledge about how to protect liver from injury and mechanisms underlying liver wound healing in addition to the pathogenesis and etiology of liver disease. Previous studies show that hepatocyte apoptosis is a profound pathological feature of various liver-related clinical conditions such as liver ischemia/reperfusion, drug-induced liver injury, and chronic liver diseases such as nonalcoholic fatty liver disease. Up to date, it is largely unknown how liver is healed from apoptosis-associated liver injury and what molecules can promote liver to regenerate from apoptosis-associated liver injury. In preliminary studies, we developed a novel triple-transgenic (3xTg) mouse model, namely, 3xTg-iHAP (inducible hepatocyte specific apoptosis phenotype) mice. We showed that 3xTg-iHAP mice harbor a set of transgenes for induction of apoptosis in hepatocyte specific manner. Using 3xTg-iHAP mice, we have found that transient hepatocyte apoptosis subsequently leads to liver inflammatory injury followed by liver regeneration and healing through a mitogenic process. Furthermore, we found that hepatocyte apoptosis-induced inflammatory injury is associated with increase in milk fat globule-EGF factor 8 (MFG-E8) in liver parenchymal cells nearby damaged hepatocytes. MFG-E8 is a trophic glycoprotein. We and others have shown that MFG-E8 preserves tissue homeostasis, protects against tissue injury, attenuates inflammation in intestines and pancreas. Recently, it has been reported that hepatic MFG-E8 plays a protective role in attenuation of fatty liver and fibrosis. However, it remains unknown that whether and how MFG-E8 is involved in repairing liver from apoptosis-induced inflammatory injury in steatosis and non-steatosis conditions and how MFG-E8 expression is regulated in the liver upon pathological conditions such as hepatocyte apoptosis-associated inflammatory injury and fatty liver. Thus, we will address these two fundamental questions in this MERIT award application by focusing on three Specific Aims: (1) To study the role of MFG-E8 in regulation of hepatocyte apoptosis-induced liver wound-healing response; (2) To elucidate how liver pathophysiological conditions influence Mfge8 gene expression in the liver; and (3) To examine the therapeutic effect of MFG-E8 on promoting healing of severe fatty liver from hepatocyte apoptosis- induced injury. By accomplishing these aims, we will advance our understanding of how MFG-E8 promotes liver regeneration upon inflammatory injury and how pathological conditions such as apoptosis-associated liver injury and steatosis regulate Mfge8 gene expression. Our study will elucidate insights into novel therapeutic strategies to promote liver wound healing in various pathological conditions.