Molecular Mechanisms of Autophagy and Implications in Liver Diseases

Overview

Journal Liver Res

Date 2025 Feb 17

PMID 39959698

Authors

Yuankai Wu

Hayden Weng Siong Tan

Jin-Yi Lin

Han-Ming Shen

Haihe Wang

Guang Lu

Affiliations

Soon will be listed here.

Abstract

Autophagy is a highly conserved process in which cytosolic contents are degraded by the lysosome, which plays an important role in energy and nutrient balance, and protein or organelle quality control. The liver is the most important organ for metabolism. Studies to date have revealed a significant role of autophagy in the maintenance of liver homeostasis under basal and stressed conditions, and the impairment of autophagy has been closely linked to various liver diseases. Therefore, a comprehensive understanding of the roles of autophagy in liver diseases may help in the development of therapeutic strategies via targeting autophagy. In this review, we will summarize the latest understanding of the molecular mechanisms of autophagy and systematically discuss its implications in various liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, viral hepatitis, hepatocellular carcinoma, and acetaminophen-induced liver injury.

References

Macovei A, Petrareanu C, Lazar C, Florian P, Branza-Nichita N . Regulation of hepatitis B virus infection by Rab5, Rab7, and the endolysosomal compartment. J Virol. 2013; 87(11):6415-27. PMC: 3648082. DOI: 10.1128/JVI.00393-13. View

Shrivastava S, Bhanja Chowdhury J, Steele R, Ray R, Ray R . Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J Virol. 2012; 86(16):8705-12. PMC: 3421755. DOI: 10.1128/JVI.00616-12. View

Kisseleva T, Brenner D . Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2020; 18(3):151-166. DOI: 10.1038/s41575-020-00372-7. View

Martinez-Lopez N, Garcia-Macia M, Sahu S, Athonvarangkul D, Liebling E, Merlo P . Autophagy in the CNS and Periphery Coordinate Lipophagy and Lipolysis in the Brown Adipose Tissue and Liver. Cell Metab. 2015; 23(1):113-27. PMC: 4715637. DOI: 10.1016/j.cmet.2015.10.008. View

Fracchiolla D, Chang C, Hurley J, Martens S . A PI3K-WIPI2 positive feedback loop allosterically activates LC3 lipidation in autophagy. J Cell Biol. 2020; 219(7). PMC: 7337497. DOI: 10.1083/jcb.201912098. View

Bakula D, Muller A, Zuleger T, Takacs Z, Franz-Wachtel M, Thost A . WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Nat Commun. 2017; 8:15637. PMC: 5460038. DOI: 10.1038/ncomms15637. View

Qian H, Chao X, Williams J, Fulte S, Li T, Yang L . Autophagy in liver diseases: A review. Mol Aspects Med. 2021; 82:100973. PMC: 9585624. DOI: 10.1016/j.mam.2021.100973. View

Ravenhill B, Boyle K, von Muhlinen N, Ellison C, Masson G, Otten E . The Cargo Receptor NDP52 Initiates Selective Autophagy by Recruiting the ULK Complex to Cytosol-Invading Bacteria. Mol Cell. 2019; 74(2):320-329.e6. PMC: 6477152. DOI: 10.1016/j.molcel.2019.01.041. View

Bartolini D, Dallaglio K, Torquato P, Piroddi M, Galli F . Nrf2-p62 autophagy pathway and its response to oxidative stress in hepatocellular carcinoma. Transl Res. 2017; 193:54-71. DOI: 10.1016/j.trsl.2017.11.007. View

10.

Liang S, Zhong Z, Kim S, Uchiyama R, Roh Y, Matsushita H . Murine macrophage autophagy protects against alcohol-induced liver injury by degrading interferon regulatory factor 1 (IRF1) and removing damaged mitochondria. J Biol Chem. 2019; 294(33):12359-12369. PMC: 6699832. DOI: 10.1074/jbc.RA119.007409. View

11.

Tan H, Lu G, Shen H . Autophagic secretion of mitochondria (ASM): an alternative way for getting rid of damaged mitochondria. Autophagy. 2022; 19(2):739-741. PMC: 9851247. DOI: 10.1080/15548627.2022.2107310. View

12.

Ohsumi Y . Historical landmarks of autophagy research. Cell Res. 2013; 24(1):9-23. PMC: 3879711. DOI: 10.1038/cr.2013.169. View

13.

Ichimura Y, Waguri S, Sou Y, Kageyama S, Hasegawa J, Ishimura R . Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell. 2013; 51(5):618-31. DOI: 10.1016/j.molcel.2013.08.003. View

14.

Nascimbeni A, Codogno P, Morel E . Phosphatidylinositol-3-phosphate in the regulation of autophagy membrane dynamics. FEBS J. 2016; 284(9):1267-1278. DOI: 10.1111/febs.13987. View

15.

Schulze R, Rasineni K, Weller S, Schott M, Schroeder B, Casey C . Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7. Hepatol Commun. 2018; 1(2):140-152. PMC: 5721426. DOI: 10.1002/hep4.1021. View

16.

Igusa Y, Yamashina S, Izumi K, Inami Y, Fukada H, Komatsu M . Loss of autophagy promotes murine acetaminophen hepatotoxicity. J Gastroenterol. 2011; 47(4):433-43. DOI: 10.1007/s00535-011-0500-0. View

17.

Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R . Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2015; 63(1):173-84. PMC: 4688087. DOI: 10.1002/hep.28251. View

18.

Rinella M, Sanyal A . Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol. 2016; 13(4):196-205. DOI: 10.1038/nrgastro.2016.3. View

19.

Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T . Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. Int J Cancer. 2011; 131(3):548-57. DOI: 10.1002/ijc.26374. View

20.

Deter R, Baudhuin P, DE DUVE C . Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J Cell Biol. 1967; 35(2):C11-6. PMC: 2107130. DOI: 10.1083/jcb.35.2.c11. View