Cathepsin B inactivation attenuates hepatocyte apoptosis and liver damage in steatotic livers after cold ischemia-warm reperfusion injury

American Journal of Physiology - Gastrointestinal and Liver Physiology - Tập 288 Số 2 - Trang G396-G402 - 2005
Edwina Baskin-Bey1, Ali Canbay1, Steven F. Bronk1, Nathan W. Werneburg1, Maria Eugenia Guicciardi1, Scott L. Nyberg1, Greg J. Barritt1
1Mayo Clinic, College of Medicine, Rochester, Minnesota

Tóm tắt

Hepatic steatosis predisposes the liver to cold ischemia-warm reperfusion (CI/WR) injury by unclear mechanisms. Because hepatic steatosis has recently been associated with a lysosomal pathway of apoptosis, our aim was to determine whether this cell-death pathway contributes to CI/WR injury of steatotic livers. Wild-type and cathepsin B-knockout ( Ctsb −/−) mice were fed the methionine/choline-deficient (MCD) diet for 2 wk to induce hepatic steatosis. Mouse livers were stored in the University of Wisconsin solution for 24 h at 4°C and reperfused for 1 h at 37°C in vitro. Immunofluorescence analysis of the lysosomal enzymes cathepsin B and D showed a punctated intracellular pattern consistent with lysosomal localization in wild-type mice fed a standard diet after CI/WR injury. In contrast, cathepsin B and D fluorescence became diffuse in livers from wild-type mice fed MCD diet after CI/WR, indicating that lysosomal permeabilization had occurred. Hepatocyte apoptosis was rare in both normal and steatotic livers in the absence of CI/WR injury but increased in wild-type mice fed an MCD diet and subjected to CI/WR injury. In contrast, hepatocyte apoptosis and liver damage were reduced in Ctsb −/− and cathepsin B inhibitor-treated mice fed the MCD diet following CI/WR injury. In conclusion, these findings support a prominent role for the lysosomal pathway of apoptosis in steatotic livers following CI/WR injury.

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Thông tin xuất bản

American Journal of Physiology - Gastrointestinal and Liver Physiology

Tập 288 Số 2

G396-G402

Thông tin tác giả