Targeting autophagy for the treatment of liver diseases

Abstract

Autophagy is a lysosomal degradation pathway that can degrade bulk cytoplasm and superfluous or damaged organelles, such as mitochondria, to maintain cellular homeostasis. It is now known that dysregulation of autophagy can cause pathogenesis of numerous human diseases. Here, we discuss the critical roles that autophagy plays in the pathogenesis of liver diseases such as non-alcoholic and alcoholic fatty liver, drug-induced liver injury, protein aggregate-related liver diseases, viral hepatitis, fibrosis, aging and liver cancer. In particular, we discuss the emerging therapeutic potential by pharmacological modulation of autophagy for these liver diseases.

Figure 1. Induction of autophagy by rapamcyin inhibits acute ethanol-induced steatosis

C57BL/6J mice were treated with ethanol (4.5 g/kg) or ethanol plus rapamycin (2 mg/kg) for 16 hours. Cryosection of livers were prepared and stained with Bodipy 581/591-C11 (50 nM) followed by confocal microscopy.

Figure 2. Induction of autophagy by rapamcyin inhibits APAP-induced liver injury

C57BL/6J mice were treated with APAP (500 mg/kg) or APAP plus rapamycin (2 mg/kg) for 6 hours. Tissue sections were stained with hematoxylin and eosine (H&E, A–B). Panel A shows typical central lobule necrotic cells with vacuolization, cell swelling and nuclear disintegration in APAP-treated mice, which are all eliminated by rapamycin (B). (C) TUNEL staining shows condensed positive nuclear DNA, and the diffuse staining in the area of necrosis indicates the release of nuclear DNA into the cytoplasm and extracellular in APAP-treated mice, whereas (D) all of these changes are inhibited by rapamycin treatment.