Peer-review started: July 9, 2020
First decision: October 6, 2020
Revised: December 10, 2020
Accepted: December 26, 2020
Article in press: December 26, 2020
Published online: January 27, 2021
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
Core Tip: Extensive investigation of autophagy is mostly based on experimental data. However there is now enough evidence to support the notion that autophagy is not only the waste recycling mechanism of the hepatocyte, but is strongly involved in the pathogenesis of almost all liver diseases. It can be either a defensive mechanism against various insults or a detrimental machinery aggravating the underlying disease. Modulation of autophagy has different consequences in the hepatocyte than in the liver macrophages, the sinusoidal endothelium or the hepatic stellate cells. There is also an opportunity for future treatment applications of autophagy manipulation.