MFGE8 protects against CCl ₄ -induced liver injury by reducing apoptosis and promoting proliferation of hepatocytes

Hao Li  ^{1   2} , Tian Zhang  ^{1   3} , Ke Wang  ^{1   2} , Meng Lu  ^{1   2} , Yonghong Guo  ⁴ , Ye Zhang  ⁵ , Zhi-Nan Chen  ^{1   2} , Huijie Bian  ^{1   2}

• ¹ Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an, China.
• ² National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi’an, China.
• ³ Department of Laboratory Medicine and Pathology, The People’s Liberation Army 926 Central Hospital, Kaiyuan, Yunnan, China.
• ⁴ Department of Infectious Diseases, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China.
• ⁵ Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi’an, China.

Abstract

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.

Keywords: ER stress; MFGE8; apoptosis; liver injury; proliferation.