CD5L-induced activation of autophagy is associated with hepatoprotection in ischemic reperfusion injury via the CD36/ATG7 axis.

Abstract

Hepatic ischemia/reperfusion (I/R) injury is a side effect of major liver surgery that is difficult to prevent. I/R injury induces metabolic strain on hepatocytes and limits the tolerable ischemia during liver resection, as well as preservation times during transplantation. Additionally, I/R injury induces apoptosis in hepatocytes. CD5-like (CD5L), an inducer of autophagy, is a soluble scavenger cysteine-rich protein that modulates hepatocyte apoptosis. The aim of the present study was to determine if pharmacologic CD5L was protective against hepatic ischemia-reperfusion injury. Hepatocytes were subjected to I/R culture conditions, and apoptosis and caspase family activity were measured after I/R to model hepatic injury. Treatment with recombinant CD5L significantly suppressed apoptosis and caspase activity through modulating cellular autophagy to maintain activation of the cluster of differentiation 36 (CD36)-dependent autophagy-related 7 (ATG7) signaling pathway. The regulation loop between CD5L and the autophagy signaling pathway was identified to be associated with the inhibition of oxidative stress. Treatment with CD5L significantly inhibited cellular oxidative stress, which was confirmed by silencing the CD36 receptor or the autophagy related protein ATG7 using small interfering RNA, which reversed the antiapoptotic and antioxidative effects of CD5L on hepatocytes under I/R conditions. The results of the present study suggested that CD5L-mediated attenuation of hepatic I/R injury occurs through the CD36-dependent ATG7 pathway, accompanied by the inhibition of oxidative stress, which is associated with enhanced autophagy. In conclusion, the present study identifies CD5L as a novel therapeutic agent for hepatic I/R injury.