Mechanism of Liver Injury Caused by Autophagy Deficiency

Autophagy is a vital intracellular degradation process which is required for many physiological & pathological processes. Deficiency of autophagy in the liver causes severe injury characterized by increased liver function enzymes in serum & hepatocyte hyperplasia & degeneration. Mice lacking one of the key autophagy genes, such as Atg7, could also be subjected to a high mortality due to liver failure. However it is not clear how autophagy deficiency causes liver injury. The goal of this study is thus to investigate the potential mechanism of injury. A careful examination of the liver histology of the Atg7‐deficient mice indicates that there was inflammation, cell death, & significant ductular reaction. We hypothesized that there was a notable level of cholestasis, which can cause cholestatic hepatitis & thus liver injury. Indeed, further blood chemistry analysis indicated a raised level of total bile acids, cholesterol, & alkaline phosphatase. This exciting new finding suggests a molecular linker from autophagy to cholestasis regulation. Previously it has been reported that anti‐oxidative stress master gene, Nrf2, is involved in autophagy deficiency‐induced liver injury. Indeed, deletion of Nrf2 in Atg7 or Atg5‐deficient mice reversed the liver condition & corrected the injury phenotype, indicating that Nrf2 participates in the pathological changes caused by autophagy deficiency. Remarkably, co‐deletion of Nrf2 in Atg7‐deficient mice also significantly tamed the cholestatic features. These observations support the notion that Nrf2 over‐activation is the key factor in the development of cholestasis, which then cause hepatocyte apoptosis & liver injury. Autophagy deficiency can cause cholestasis, which could be responsible for the liver injury seen in the autophagy‐deficient mice.