Metabolic contribution of hepatic autophagic proteolysis: old wine in new bottles.

Pioneering work on autophagy was achieved soon after the discovery of lysosomes more than 50 years ago. Due to its prominent lysosomal activity and technical ease of handling, the liver has been at the center of continuous and vigorous investigations into autophagy. Many important discoveries, including suppression by insulin and plasma amino acids and stimulation by glucagon, have been made through in vivo and in vitro studies using perfused liver and cultured hepatocytes. The long-term controversy about the origin and nature of the autophagosome membrane has finally led to the conclusion of "phagophore," through extensive molecular cell biological approaches enlightened by the discovery of autophagy-essential ATG genes. Furthermore, recent studies using liver-specific autophagy-deficient mice have thrown light on the unique role of a selective substrate of autophagy, p62. The stabilized p62 accumulating in autophagy-deficient liver manipulates Nrf2-dependent transcription activation through specific binding to Keap1, which results in the elevated gene expression involved in detoxification. This is the first example of the dysregulation of gene expression under autophagy deficiency. Thus, basal liver autophagy makes a large contribution to the maintenance of cell homeostasis and health. Meanwhile, precise comparisons of wild-type and liver-specific autophagy-deficient mice under starvation conditions have revealed that amino acids released by autophagic degradation can be metabolized to produce glucose via gluconeogenesis for the maintenance of blood glucose, and can also be excreted to the circulation to supply serum amino acids. These results strongly confirm that induced liver autophagy plays a pivotal role in metabolic compensation. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.