A Nocito

A Rickenbacher

AD Tevar

AK Leamy

B Ravikumar

D Degli Esposti

DE Kleiner

G Serviddio

H Fang

HW Park

HY Liu

J Luo

JA Sala-Mercado

JH Wang

JL Schneider

JM Norman

JS Kim

KM Olthoff

L McCormack

L Pichard

L Yang

MA Zaouali

MJ Czaja

R Singh

S Sciarretta

S Seok

TR Peterson

X Ma

Y Lu

Cell Death and Disease

AbstractHepatic steatosis is associated with significant morbidity and mortality after liver resection and transplantation. This study focuses on the role of autophagy in regulating sensitivity of fatty livers to ischemia and reperfusion (I/R) injury. Quantitative immunohistochemistry conducted on human liver allograft biopsies showed that, the reduction of autophagy markers LC3 and Beclin-1 at 1 h after reperfusion, was correlated with hepatic steatosis and poor survival of liver transplant recipients. In animal studies, western blotting and confocal imaging analysis associated the increase in sensitivity to I/R injury with low autophagy activity in fatty livers. Screening of autophagy-related proteins showed that Atg3 and Atg7 expression levels were marked decreased, whereas calpain 2 expression was upregulated during I/R in fatty livers. Calpain 2 inhibition or knockdown enhanced autophagy and suppressed cell death. Further point mutation experiments revealed that calpain 2 cleaved Atg3 and Atg7 at Atg3Δ92–97 and Atg7Δ344–349, respectively. In vivo and in vitro overexpression of Atg3 or Atg7 enhanced autophagy and suppressed cell death after I/R in fatty livers. Collectively, calpain 2-mediated degradation of Atg3 and Atg7 in fatty livers increases their sensitivity to I/R injury. Increasing autophagy may ameliorate fatty liver damage and represent a valuable method to expand the liver donor pool.</jats:p

Q Zhao

Z Guo

W Deng

S Fu

C Zhang

M Chen

W Ju

D Wang

X He

Crossref

Calpain 2-mediated autophagy defect increases susceptibility of fatty livers to ischemia–reperfusion injury

Calpain 2-mediated autophagy defect increases susceptibility of fatty livers to ischemia–reperfusion injury

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