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.