MFGE8 Inhibits Nonalcoholic Fatty Liver Disease By Blocking ASK1-JNK/p38 Signaling

Background and Aims: Non-alcoholic fatty liver disease(NAFLD)has become the most common liver disease in the world with a prevalence at about 25% and putting subjects at high risk of cirrhosis and HCC.Milk fat globule-EGF 8(MFGE8)was shown to be a critical extracellular molecule that mediates apoptotic signaling in the pathological process of NAFLD.Mfge8 is abundantly expressed in hepatocyte and their cytoplasmic space,but its function in the pathogenesis of NAFLD has not been characterized.Approaches and Results: In our current study,hepatic MFGE8 showed a protective role in the pathogenesis of NAFLD.In an in vitro study using human liver cell line L02,we found MFGE8 overexpression significantly alleviated lipid accumulation,accompanied with the relevant genes downregulation involved in lipid metabolism and innate immune response.To further investigate the in vivo function of MFGE8 and the relevant mechanism,we constructed hepatic specific MFGE8 overexpression mice(hereafter named MFGE8-HTG),and subjected these mice and control mice to high fat diet(HFD)for 24 weeks.We found MFGE8-HTG mice had significantly improved metabolic phenotype,as reflected by fasting blood glucose and associated parameters,and decreased expression of lipid-related genes such as fatty acid synthase(FAS).Analyzing the signaling proteins,we found MFGE8-overexoression cells manifested a dramatic downregulation of apoptosis signaling regulated kinase 1(ASK1)-c-Jun Nterminal kinase(JNK)/p38 axis components.Mechanistically,immunostaining of endogenous ASK1 and MFGE8 using primary hepatocytes and labeled exogenous MFGE8 and AKS1 in L02 cell line revealed intracellular colocalization of these two proteins.Conclusion: Intracellular MFGE8 is an endogenous suppressor of NAFLD progression,and may function through interaction with apoptosis signaling regulated kinase 1(ASK1).Therefore,the maintenance of appropriate level of intracellular MFGE8 is a practical treatment strategy to NAFLD and metabolic diseases.