Autophagy in liver diseases

Abstract

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.

Keywords: Autophagy; Fatty liver disease; Fibrosis; Lipophagy; Liver sinusoidal cells; Mitophagy.

Figure 1

A simplified scheme of the macroautophagy pathways in the liver. Initiation starts with activation of the unc-51-like kinase 1 complex (ULK1, Atg1 in yeast) followed by beclin 1(Atg6 in yeast) and a subsequent cascade of Atg proteins leading to autophagosome formation where LC3 (Atg8 in yeast) is implicated. LC3 is further processed to form initially LC3-I and then LC3-II. Fusion of the autophagosomes with lysosomes form the autolysosome where acid proteases (among which cathepsins are important) and lipases degrade proteins and lipids. Initiation of autophagy is controlled by two metabolic sensors the mammalian target of rapamycin complex 1 (mTORC1) and the AMP-activated protein kinase (AMPK). mTORC1 negatively regulates autophagy inhibiting ULK1. AMPK suppresses mTORC1 activity. The long-term regulation of autophagy is carried out by transcription factor EB (TFEB), the main regulator of lysosomal biogenesis and autophagy. Under nutrient-rich conditions, mTORC1 phosphorylates TFEB and retains TFEB in the cytosol. Orange arrows: Inhibition. Green arrows: Positive regulation. For details see Ref.[21,29,31]. mTORC1: Mammalian target of rapamycin complex 1; TFEB: Transcription factor EB; ULK1: Unc-51-like kinase 1 complex.

Figure 2

Implications of autophagy in critical cellular functions in the liver. For details see text.