Role of Autophagy in Chronic Liver Inflammation and Fibrosis

Author(s): Yu-Jen Tseng, Ling Dong, Yu-Feng Liu, Nuo Xu, Wei Ma, Shu-Qiang Weng, Harry L.A. Janssen*, Sheng-Di Wu*

Journal Name: Current Protein & Peptide Science

Volume 20 , Issue 8 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Autophagy entails the removal of dysfunctional components to maintain cellular homeostasis. Over the years, studies of autophagy demonstrated its complex physiological and pathological roles in the liver. Apart from regulation of normal metabolic functions such as glycogenolysis, glycogenesis, and β-oxidation, autophagy also contributes to the modulation of various liver diseases. In this review, we provide a concise overview of the role of autophagy in regulating hepatic metabolism in healthy conditions and various chronic liver diseases. A well-rounded understanding of the role of autophagy may provide insight for future medical advancements in the field of hepatology.

Keywords: Autophagy, chronic liver inflammation, lipophagy, macroautophagy, microautophagy, fibrosis.

Schneider, J.L.; Cuervo, A.M. Liver autophagy: Much more than just taking out the trash. Nat. Rev. Gastroenterol. Hepatol., 2014, 11, 187-200.
Ueno, T.; Komatsu, M. Autophagy in the liver: Functions in health and disease. Nat. Rev. Gastroenterol. Hepatol., 2017, 14, 170-184.
Mortimore, G.E.; Lardeux, B.R.; Adams, C.E. Regulation of microautophagy and basal protein turnover in rat liver. Effects of short-term starvation. J. Biol. Chem., 1988, 263, 2506-2512.
Kaushik, S.; Cuervo, A.M. Chaperones in autophagy. Pharmacol. Res., 2012, 66, 484-493.
Bandyopadhyay, U.; Kaushik, S.; Varticovski, L.; Cuervo, A.M. The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol. Cell. Biol., 2008, 28, 5747-5763.
Cuervo, A.M.; Dice, J.F. A receptor for the selective uptake and degradation of proteins by lysosomes. Science, 1996, 273, 501-503.
Yang, Z.; Klionsky, D.J. Mammalian autophagy: Core molecular machinery and signaling regulation. Curr. Opin. Cell Biol., 2010, 22, 124-131.
Mizushima, N.; Yoshimori, T.; Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol., 2011, 27, 107-132.
Novak, I.; Dikic, I. Autophagy receptors in developmental clearance of mitochondria. Autophagy, 2011, 7, 301-303.
Schworer, C.M.; Shiffer, K.A.; Mortimore, G.E. Quantitative relationship between autophagy and proteolysis during graded amino acid deprivation in perfused rat liver. J. Biol. Chem., 1981, 256, 7652-7658.
Eng, C.H.; Yu, K.; Lucas, J.; Abraham, R.T. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci. Signal., 2010, 3, ra31.
Lum, J.J.; Bauer, D.E.; Kong, M.; Thompson, C.B. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005, 120, 237-248.
Ezaki, J.; Matsumoto, N.; Takeda-Ezaki, M.; Ueno, T. Liver autophagy contributes to the maintenance of blood glucose and amino acid levels. Autophagy, 2011, 7, 727-736.
Singh, R.; Kaushik, S.; Wang, Y.; Czaja, M.J. Autophagy regulates lipid metabolism. Nature, 2009, 458, 1131-1135.
Mei, S.; Ni, H.M.; Manley, S.; Ding, W.X. Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J. Pharmacol. Exp. Ther., 2011, 339, 487-498.
Ding, W.X.; Li, M.; Chen, X.; Yin, X.M. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology, 2010, 139, 1740-1752.
Thoen, L.F.; Guimaraes, E.L.; Dolle, L.; van Grunsven, L.A. A role for autophagy during hepatic stellate cell activation. J. Hepatol., 2011, 55, 1353-1360.
Hernandez-Gea, V.; Ghiassi-Nejad, Z.; Rozenfeld, R.; Friedman, S.L. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology, 2012, 142, 938-946.
Cuervo, A.M.; Knecht, E.; Terlecky, S.R.; Dice, J.F. Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation. Am. J. Physiol., 1995, 269, C1200-C1208.
Anguiano, J.; Garner, T.P.; Mahalingam, M.; Cuervo, A.M. Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. Nat. Chem. Biol., 2013, 9, 374-382.
Fujita, N.; Morita, E.; Itoh, T.; Yoshimori, T. Recruitment of the autophagic machinery to endosomes during infection is mediated by ubiquitin. J. Cell Biol., 2013, 203, 115-128.
Komatsu, M.; Waguri, S.; Koike, M.; Tanaka, K. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell, 2007, 131, 1149-1163.
Mathew, R.; Karp, C.M.; Beaudoin, B.; White, E. Autophagy suppresses tumorigenesis through elimination of p62. Cell, 2009, 137, 1062-1075.
Madrigal-Matute, J.; Cuervo, A.M. Regulation of liver metabolism by autophagy. Gastroenterology, 2016, 150, 328-339.
Czaja, M.J.; Ding, W.; Donohue, T.M.; Yin, X. Functions of autophagy in normal and diseased liver. Autophagy, 2014, 9, 1131-1158.
Gual, P.; Gilgenkrantz, H.; Lotersztajn, S. Autophagy in chronic liver diseases: The two faces of Janus. Am. J. Physiol. Cell Physiol., 2017, 312, C263-C273.
Kaushik, S.; Massey, A.C.; Mizushima, N.; Cuervo, A.M. Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Mol. Biol. Cell, 2008, 19, 2179-2192.
Chuang, S.Y.; Yang, C.H.; Chou, C.C.; Hsu, L.C. TLR-induced PAI-2 expression suppresses IL-1beta processing via increasing autophagy and NLRP3 degradation. Proc. Natl. Acad. Sci. USA, 2013, 110, 16079-16084.
Liao, X.; Sluimer, J.C.; Wang, Y.; Tabas, I. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab., 2012, 15, 545-553.
Lodder, J.; Denaes, T.; Chobert, M.N.; Teixeira-Clerc, F. Macrophage autophagy protects against liver fibrosis in mice. Autophagy, 2015, 11, 1280-1292.
Liu, K.; Zhao, E.; Ilyas, G.; Czaja, M.J. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy, 2015, 11, 271-284.
Denaes, T.; Lodder, J.; Chobert, M.N.; Teixeira-Clerc, F. The cannabinoid receptor 2 protects against alcoholic liver disease via a macrophage autophagy-dependent pathway. Sci. Rep., 2016, 6, 28806.
Marra, F.; Lotersztajn, S. Pathophysiology of NASH: Perspectives for a targeted treatment. Curr. Pharm. Des., 2013, 19, 5250-5269.
Yang, L.; Li, P.; Fu, S.; Hotamisligil, G.S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab., 2010, 11, 467-478.
Tran, A.; Gual, P. Non-alcoholic steatohepatitis in morbidly obese patients. Clin. Res. Hepatol. Gastroenterol., 2013, 37, 17-29.
Schneider, J.L.; Suh, Y.; Cuervo, A.M. Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation. Cell Metab., 2014, 20, 417-432.
Koga, H.; Kaushik, S.; Cuervo, A.M. Altered lipid content inhibits autophagic vesicular fusion. FASEB J., 2010, 24, 3052-3065.
Cui, M.; Yu, H.; Wang, J.; Li, J. Chronic caloric restriction and exercise improve metabolic conditions of dietary-induced obese mice in autophagy correlated manner without involving AMPK. J. Diabetes Res., 2013, 2013, 852754.
Wang, S.; Pacher, P.; De Lisle, R.C.; Ding, W.X. A mechanistic review of cell death in alcohol-induced liver injury. Alcohol. Clin. Exp. Res., 2016, 40, 1215-1223.
Ding, W.X.; Li, M.; Yin, X.M. Selective taste of ethanol-induced autophagy for mitochondria and lipid droplets. Autophagy, 2011, 7, 248-249.
Wu, D.; Wang, X.; Zhou, R.; Cederbaum, A. CYP2E1 enhances ethanol-induced lipid accumulation but impairs autophagy in HepG2 E47 cells. Biochem. Biophys. Res. Commun., 2010, 402, 116-122.
Levine, B.; Mizushima, N.; Virgin, H.W. Autophagy in immunity and inflammation. Nature, 2011, 469, 323-335.
Sir, D.; Ou, J.H. Autophagy in viral replication and pathogenesis. Mol. Cells, 2010, 29, 1-7.
Tian, Y.; Sir, D.; Kuo, C.F.; Ou, J.H. Autophagy required for hepatitis B virus replication in transgenic mice. J. Virol., 2011, 85, 13453-13456.
Li, J.; Liu, Y.; Wang, Z.; Yuan, Z. Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J. Virol., 2011, 85, 6319-6333.
Sir, D.; Tian, Y.; Chen, W.L.; Ou, J.H. The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc. Natl. Acad. Sci. USA, 2010, 107, 4383-4388.
Tang, H.; Da, L.; Mao, Y.; Zhao, M. Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression. Hepatology, 2009, 49, 60-71.
Sir, D.; Chen, W.L.; Choi, J.; Ou, J.H. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology, 2008, 48, 1054-1061.
Ait-Goughoulte, M.; Kanda, T.; Meyer, K.; Ray, R. Hepatitis C virus genotype 1a growth and induction of autophagy. J. Virol., 2008, 82, 2241-2249.
Dreux, M.; Gastaminza, P.; Wieland, S.F.; Chisari, F.V. The autophagy machinery is required to initiate hepatitis C virus replication. Proc. Natl. Acad. Sci. USA, 2009, 106, 14046-14051.
Su, W.C.; Chao, T.C.; Huang, Y.L.; Lai, M.M. Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J. Virol., 2011, 85, 10561-10571.
Shrivastava, S.; Bhanja, C.J.; Steele, R.; Ray, R.B. Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J. Virol., 2012, 86, 8705-8712.
Ke, P.Y.; Chen, S.S. Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro. J. Clin. Invest., 2011, 121, 37-56.
Gosert, R.; Egger, D.; Lohmann, V.; Moradpour, D. Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. J. Virol., 2003, 77, 5487-5492.
Guevin, C.; Manna, D.; Belanger, C.; Labonte, P. Autophagy protein ATG5 interacts transiently with the hepatitis C virus RNA polymerase (NS5B) early during infection. Virology, 2010, 405, 1-7.
Taguwa, S.; Kambara, H.; Fujita, N.; Matsuura, Y. Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating hepatitis C virus. J. Virol., 2011, 85, 13185-13194.
Shrivastava, S.; Raychoudhuri, A.; Steele, R.; Ray, R.B. Knockdown of autophagy enhances the innate immune response in hepatitis C virus-infected hepatocytes. Hepatology, 2011, 53, 406-414.
Ding, W.X.; Guo, F.; Ni, H.M.; Yin, X.M. Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. J. Cell Biol., 2012, 287, 42379-42388.
Lomas, D.A.; Evans, D.L.; Finch, J.T.; Carrell, R.W. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature, 1992, 357, 605-607.
Stoller, J.K.; Aboussouan, L.S. A review of alpha1-antitrypsin deficiency. Am. J. Respir. Crit. Care Med., 2012, 185, 246-259.
Teckman, J.H.; Perlmutter, D.H. Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am. J. Physiol. Gastrointest. Liver Physiol., 2000, 279, G961-G974.
Hidvegi, T.; Ewing, M.; Hale, P.; Perlmutter, D.H. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science, 2010, 329, 229-232.
Mallat, A.; Lodder, J.; Teixeira-Clerc, F.; Lotersztajn, S. Autophagy: A multifaceted partner in liver fibrosis. BioMed Res. Int., 2014, 2014, 869390.
Lotersztajn, S.; Julien, B.; Teixeira-Clerc, F.; Mallat, A. Hepatic fibrosis: Molecular mechanisms and drug targets. Annu. Rev. Pharmacol. Toxicol., 2005, 45, 605-628.
Mallat, A.; Lotersztajn, S. Cellular mechanisms of tissue fibrosis. 5. Novel insights into liver fibrosis. Am. J. Physiol. Cell Physiol., 2013, 305, C789-C799.
Mathew, R.; Kongara, S.; Beaudoin, B.; White, E. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev., 2007, 21, 1367-1381.
Liang, X.H.; Jackson, S.; Seaman, M.; Levine, B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature, 1999, 402, 672-676.
Inami, Y.; Waguri, S.; Sakamoto, A.; Komatsu, M. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J. Cell Biol., 2011, 193, 275-284.
Yang, X.; Yu, D.; Yan, F.; Wei, L. The role of autophagy induced by tumor microenvironment in different cells and stages of cancer. Cell Biosci., 2015, 5, 14.
Sun, K.; Guo, X.; Zhao, Q.; Wei, L. Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats. Cell Death Dis., 2013, 4, e501.
Takamura, A.; Komatsu, M.; Hara, T.; Mizushima, N. Autophagy-deficient mice develop multiple liver tumors. Genes Dev., 2011, 25, 795-800.
Xu, Y.; An, Y.; Wang, Y.; Li, X. miR-101 inhibits autophagy and enhances cisplatin-induced apoptosis in hepatocellular carcinoma cells. Oncol. Rep., 2013, 29, 2019-2024.
Decaens, T.; Luciani, A.; Itti, E.; Duvoux, C. Phase II study of sirolimus in treatment-naive patients with advanced hepatocellular carcinoma. Dig. Liver Dis., 2012, 44, 610-616.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 07 July, 2019
Page: [817 - 822]
Pages: 6
DOI: 10.2174/1389203720666190305165203
Price: $65

Article Metrics

PDF: 71
HTML: 10