MFGE8 protects against CCl4‐induced liver injury by reducing apoptosis and promoting proliferation of hepatocytes

• Published in: Journal of cellular physiology 2019-09, Vol.234 (9), p.16463-16474
• Main Authors: Li, Hao, Zhang, Tian, Wang, Ke, Lu, Meng, Guo, Yonghong, Zhang, Ye, Chen, Zhi‐Nan, Bian, Huijie
• Format: Article
• Language: English
• Subjects: AKT protein; Animal tissues; Apoptosis; Carbon tetrachloride; CCL4 protein; Chemical compounds; Cirrhosis; Cytokines; ER stress; Fibrosis; Hepatitis; Hepatocellular carcinoma; Hepatocytes; Immunohistochemistry; Injury prevention; Liver; Liver cancer; Liver cirrhosis; liver injury; MAP kinase; MFGE8; Mice; Milk fat globule membranes; Pharmacology; Phosphorylation; proliferation; Prolongation; Transaminase
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.28314

Milk fat globule‐EGF factor 8 (MFGE8) has been reported to play various roles in acute injury and inflammation response. However, the role of MFGE8 in liver injury is poorly investigated. The present research was designed to clarify the expression and function of MFGE8 in carbon tetrachloride (CCl4)‐induced liver injury. Using serum cytokine arrays, we selected a promising cytokine MFGE8 as the candidate in the process of hepatitis‐fibrosis‐hepatocellular carcinoma (HCC) progression, based on the elevated expression in both hepatic fibrosis and HCC models. We validated the increased expression of MFGE8 in liver tissues and serum samples of acute and chronic CCl4‐induced mice. Immunohistochemistry staining of mouse liver tissues indicated that elevated MFGE8 expression was mainly derived from the injured hepatocytes. In addition, MFGE8 expression in the supernatant of primary hepatocytes was accumulated with prolongation of culture time, and CCl4 treatment further increased the expression of MFGE8. Moreover, a strong correlation between serum MFGE8 expression and liver transaminase activities suggested that MFGE8 may be a novel candidate in liver injury. Intriguingly, mice pretreated with MFGE8 were protected from CCl4‐induced liver injury through antiapoptosis role in the early stage and proproliferation role in the late stage. MFGE8 reduced apoptosis by inhibiting the activation of IRE1α/ASK1/JNK pathway and promoted proliferation by phosphorylation of ERK and AKT. Moreover, serum MFGE8 expression was increased in hepatitis patients while decreased in liver cirrhosis patients. All the results suggest MFGE8 as a novel marker and promising therapeutic agent of liver injury. Protective role of milk fat globule‐EGF factor 8 (MFGE8) in acute liver injury by regulation of apoptosis and proliferation. In the early stage, MFGE8 reduced apoptosis of hepatocytes through inhibiting IRE1α/ASK1/JNK proapoptotic pathway. In the late stage, MFGE8 promoted proliferation of hepatocytes by phosphorylation of AKT and ERK.