Autophagy in the liver: functions in health and disease

Key Points Autophagy was first discovered in rodent liver tissues in 1960s, and early studies of autophagy in liver tissues and hepatocytes revealed regulation via hormones and amino acids In the 1990s, autophagy-related genes essential for autophagosome formation were identified, advancing our understanding of the molecular mechanisms of autophagy as well as its physiological roles Catabolism of glycogen granules, lipid droplets and proteins through autophagy has an effect on hepatocyte metabolic pathways including glycogenolysis, gluconeogenesis and β-oxidation Hepatic metabolic processes mediated by autophagy are regulated by a series of transcription factors including CREB, TFEB, PPARα and NRF2 Impaired liver autophagy caused by HCV and HBV infection and lipid toxicity is closely related to the pathogenesis of liver diseases such as NAFLD and hepatocellular carcinoma Pharmacological enhancement of autophagy attenuates clinical symptoms of α1-antitrypsin deficiency, a conformational liver disease Autophagy is a conserved process critically involved in many cellular functions. In this Review, Ueno and Komatsu discuss the role and regulation of autophagy in healthy liver and in hepatic disease states, including NAFLD, α1-antitrypsin deficiency and viral hepatitis. The concept of macroautophagy was established in 1963, soon after the discovery of lysosomes in rat liver. Over the 50 years since, studies of liver autophagy have produced many important findings. The liver is rich in lysosomes and possesses high levels of metabolic-stress-induced autophagy, which is precisely regulated by concentrations of hormones and amino acids. Liver autophagy provides starved cells with amino acids, glucose and free fatty acids for use in energy production and synthesis of new macromolecules, and also controls the quality and quantity of organelles such as mitochondria. Although the efforts of early investigators contributed markedly to our current knowledge of autophagy, the identification of autophagy-related genes represented a revolutionary breakthrough in our understanding of the physiological roles of autophagy in the liver. A growing body of evidence has shown that liver autophagy contributes to basic hepatic functions, including glycogenolysis, gluconeogenesis and β-oxidation, through selective turnover of specific cargos controlled by a series of transcription factors. In this Review, we outline the history of liver autophagy study, and then describe the roles of