Autophagy in liver diseases

Abstract

Autophagy, or cellular self-digestion, is a cellular pathway crucial for development, differentiation, survival, and homeostasis. Its implication in human diseases has been highlighted during the last decade. Recent data show that autophagy is involved in major fields of hepatology. In liver ischemia reperfusion injury, autophagy mainly has a prosurvival activity allowing the cell for coping with nutrient starvation and anoxia. During hepatitis B or C infection, autophagy is also increased but subverted by viruses for their own benefit. In hepatocellular carcinoma, the autophagy level is decreased. In this context, autophagy has an anti-tumor role and therapeutic strategies increasing autophagy, as rapamycin, have a beneficial effect in patients. Moreover, in hepatocellular carcinoma, Beclin-1 level, an autophagy protein, has a prognostic significance. In α-1-antitrypsin deficiency, the aggregation-prone ATZ protein accumulates in the endoplasmic reticulum. This activates the autophagic response which aims at degrading mutant ATZ. Some FDA-approved drugs which enhance autophagy and the disposal of aggregation-prone proteins may be useful in α-1-antitrypsin deficiency. Following alcohol consumption, autophagy is decreased in liver cells, likely due to a decrease in intracellular 5'-AMP-activated protein kinase (AMPk) and due to an alteration in vesicle transport in hepatocytes. This decrease in autophagy contributes to the formation of Mallory-Denk bodies and to liver cell death. Hepatic autophagy is defective in the liver in obesity and its upregulation improves insulin sensitivity.

Changes in Autophagic Response in Patients with Chronic Hepatitis C Virus Infection

“…[5][6][7][8][9][10][11] In vitro, HCV induced autophagosome formation but was not able to enhance autophagic protein degradation suggesting an inefficient fusion between autophagosomes and lysosomes. 2,6 The results of ultrastructural morphometry obtained in the present study could indirectly support this view. Indeed, in the liver of CHC patients, we observed a strong increase in the number of autophagic vesicles without augmentation in the number of mature lysosomes that could attest such a blockade of the last step of autophagy.…”

“…In conclusion, autophagy is altered in hepatocytes from CHC patients, likely due to a blockade of the last step of the autophagic Autophagy is a major cellular pathway for the degradation of long-lived proteins, constituents of cytoplasm and organelles. 1,2 During autophagy, double-membrane vesicles form to sequester part of the cytoplasm. These double-membrane vesicles, also known as autophagosomes, subsequently fuse with lysosomes to form autolysosomes for the degradation of their contents for recycling.…”

“…[5][6][7][8][9][10][11] However, the relevance of such findings in vivo remains unknown because autophagy has never been assessed in chronic hepatitis C (CHC) patients. 2,4 The aims of the present study were to evaluate the autophagic response in CHC patients, and to identify factors influencing the autophagy level in such patients.…”

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

“…Autophagy plays an essential role in cellular metabolism and homeostasis by degrading both long‐lived cytoplasmic proteins and dysfunctional organelles via lysosome‐dependent machinery (Klionsky & Emr, 2000; Rautou et al., 2010). Recently, the potential involvement of autophagy in aging and aging‐associated organ injuries has become evident.…”

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

“…62 The postulated mechanism of decreased autophagy levels in alcohol abuse may be due to decreased adenosine monophosphate-activated protein linase (AMPk) activity with consequent decrease in autophagy via the mTOR pathway and altered intracellular vesicle transport due to altered functions of microtubules and microfilaments. 63 The mTOR inhibitors may be beneficial in alcoholic liver disease by inducing apoptosis, improving the clearance of proteins from the hepatocytes as well as suppressing lipogenesis.…”