Key Points
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Autophagy contributes to the maintenance of the energetic balance, participates in hepatocyte quality control and aids in the defence against exogenous pathogens and conditions that cause cellular toxicity in the liver
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The different autophagic pathways that coexist in the liver are in dynamic intercommunication with one another, enabling a coordinated response to maintain homeostasis
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Failure to properly execute the autophagic program leaves hepatocytes vulnerable to stressors and unable to accommodate the extreme energetic demands of this organ
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Autophagy malfunction underlies the pathogenesis of common liver diseases, including metabolic disorders, protein conformational diseases, viral infection and carcinogenesis
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Chemical modulation of autophagy has proven to be beneficial in certain liver pathologies, although manipulation of autophagy needs to be customized according to the status of the autophagic pathway in each disease state
Abstract
Studies performed in the liver in the 1960s led to the identification of lysosomes and the discovery of autophagy, the process by which intracellular proteins and organelles are degraded in lysosomes. Early studies in hepatocytes also uncovered how nutritional status regulates autophagy and how various circulating hormones modulate the activity of this catabolic process in the liver. The intensive characterization of hepatic autophagy over the years has revealed that lysosome-mediated degradation is important not only for maintaining liver homeostasis in normal physiological conditions, but also for an adequate response of this organ to stressors such as proteotoxicity, metabolic dysregulation, infection and carcinogenesis. Autophagic malfunction has also been implicated in the pathogenesis of common liver diseases, suggesting that chemical manipulation of this process might hold potential therapeutic value. In this Review—intended as an introduction to the topic of hepatic autophagy for clinical scientists—we describe the different types of hepatic autophagy, their role in maintaining homeostasis in a healthy liver and the contribution of autophagic malfunction to liver disease.
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References
Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).
Yang, Z. & Klionsky, D. J. Mammalian autophagy: core molecular machinery and signaling regulation. Curr. Opin. Cell Biol. 22, 124–131 (2010).
Ciechanover, A. Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Biochim. Biophys. Acta 1824, 3–13 (2012).
De Duve, C. & Wattiaux, R. Functions of lysosomes. Annu. Rev. Physiol. 28, 435–492 (1966).
Mizushima, N. & Klionsky, D. J. Protein turnover via autophagy: implications for metabolism. Annu. Rev. Nutr. 27, 19–40 (2007).
Singh, R. & Cuervo, A. M. Autophagy in the cellular energetic balance. Cell Metab. 13, 495–504 (2011).
Deter, R. L., Baudhuin, P. & De Duve, C. Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J. Cell Biol. 35, C11–C16 (1967).
Mortimore, G. E. & Schworer, C. M. Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature 270, 174–176 (1977).
Mortimore, G. & Mondon, C. E. Inhibition by insulin of valine turnover in liver. J. Biol. Chem. 245, 2375–2383 (1970).
Klionsky, D. J. et al. A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5, 539–545 (2003).
Mizushima, N., Sugita, H., Yoshimori, T. & Ohsumi, Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J. Biol. Chem. 273, 33889–33892 (1998).
Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell. Dev. Biol. 27, 107–132 (2011).
Novak, I. & Dikic, I. Autophagy receptors in developmental clearance of mitochondria. Autophagy 7, 301–303 (2011).
Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 (2011).
Berg, T. O., Fengsrud, M., Stromhaug, P. E., Berg, T. & Seglen, P. O. Isolation and characterization of rat liver amphisomes. Evidence for fusion of autophagosomes with both early and late endosomes. J. Biol. Chem. 273, 21883–21892 (1998).
Yang, Z. & Klionsky, D. J. Permeases recycle amino acids resulting from autophagy. Autophagy 3, 149–150 (2007).
Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334, 678–683 (2011).
Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).
Yamamoto, A., Cremona, M. & Rothman, J. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J. Cell Biol. 172, 719–731 (2006).
Kroemer, G., Marino, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280–293 (2010).
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. 263, 2506–2512 (1988).
Sakai, Y., Koller, A., Rangell, L., Keller, G. & Subramani, S. Peroxisome degradation by microautophagy in Pichia pastoris. Identification of specific steps and morphological intermediates. J. Cell Biol. 141, 625–636 (1998).
Sahu, R. et al. Microautophagy of cytosolic proteins by late endosomes. Dev. Cell 20, 131–139 (2011).
Raiborg, C. & Stenmark, H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445–452 (2009).
Rusten, T. E. et al. ESCRTs and Fab1 regulate distinct steps of autophagy. Curr. Biol. 17, 1817–1825 (2007).
Dice, J. F. Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem. Sci. 15, 305–309 (1990).
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. 28, 5747–5763 (2008).
Cuervo, A. M. & Dice, J. F. A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273, 501–503 (1996).
Kaushik, S. & Cuervo, A. M. Chaperones in autophagy. Pharmacol. Res. 66, 484–493 (2012).
Kaushik, S. & Cuervo, A. M. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell. Biol. 22, 407–417 (2012).
Arias, E. & Cuervo, A. M. Chaperone-mediated autophagy in protein quality control. Curr. Opin. Cell Biol. 23, 184–189 (2011).
Kiffin, R., Christian, C. J., Knecht, E. & Cuervo, A. M. Activation of chaperone-mediated autophagy during oxidative stress. Mol. Biol. Cell 15, 4829–4840 (2004).
Massey, A. C., Kaushik, S., Sovak, G., Kiffin, R. & Cuervo, A. M. Consequences of the selective blockage of chaperone-mediated autophagy. Proc. Natl Acad. Sci. USA 103, 5905–5910 (2006).
Matsui, Y. et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res. 100, 914–922 (2007).
Eng, C. H., Yu, K., Lucas, J., White, E. & Abraham, R. T. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci. Signal. 3, ra31 (2010).
Lum, J. et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237–248 (2005).
Ezaki, J. et al. Liver autophagy contributes to the maintenance of blood glucose and amino acid levels. Autophagy 7, 727–736 (2011).
Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).
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. 269, C1200–C1208 (1995).
Anguiano, J. et al. Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. Nat. Chem. Biol. 9, 374–382 (2013).
Finn, P. F. & Dice, J. F. Ketone bodies stimulate chaperone-mediated autophagy. J. Biol. Chem. 280, 25864–25870 (2005).
Cuervo, A. M. & Dice, J. F. Regulation of lamp2a levels in the lysosomal membrane. Traffic 1, 570–583 (2000).
Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).
Ding, W. X. et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology 139, 1740–1752 (2010).
Mei, S. et al. Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J. Pharmacol. Exp. Ther. 339, 487–498 (2011).
O'Rourke, E. J. & Ruvkun, G. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat. Cell Biol. 15, 668–676 (2013).
Lapierre, L. R., Gelino, S., Melendez, A. & Hansen, M. Autophagy and lipid metabolism coordinately modulate life span in germline-less, C. elegans. Curr. Biol. 21, 1507–1514 (2011).
Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647–658 (2013).
Thoen, L. F. et al. A role for autophagy during hepatic stellate cell activation. J. Hepatol. 55, 1353–1360 (2011).
Hernandez-Gea, V. et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938–946 (2012).
Kotoulas, O. B., Kalamidas, S. A. & Kondomerkos, D. J. Glycogen autophagy in glucose homeostasis. Pathol. Res. Pract. 202, 631–638 (2006).
Jiang, S. et al. Starch binding domain-containing protein 1/genethonin 1 is a novel participant in glycogen metabolism. J. Biol. Chem. 285, 34960–34971 (2010).
Jiang, S., Wells, C. D. & Roach, P. J. Starch-binding domain-containing protein 1 (Stbd1) and glycogen metabolism: identification of the Atg8 family interacting motif (AIM) in Stbd1 required for interaction with GABARAPL1. Biochem. Biophys. Res. Commun. 413, 420–425 (2011).
Takikita, S. et al. The values and limits of an in vitro model of Pompe disease: the best laid schemes o' mice an' men. Autophagy 5, 729–731 (2009).
Lv, L. et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol. Cell 42, 719–730 (2011).
Mathew, R. et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062–1075 (2009).
Komatsu, M. et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007).
Twig, G. et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433–446 (2008).
Kim, I., Rodriguez-Enriquez, S. & Lemasters, J. J. Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys. 462, 245–253 (2007).
Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008).
Twig, G. & Shirihai, O. S. The interplay between mitochondrial dynamics and mitophagy. Antioxid. Redox Signal. 14, 1939–1951 (2011).
Schweers, R. L. et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc. Natl Acad. Sci. USA 104, 19500–19505 (2007).
Glick, D. et al. BNip3 regulates mitochondrial function and lipid metabolism in the liver. Mol. Cell. Biol. 32, 2570–2584 (2012).
Ding, W. X. et al. Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. J. Biol. Chem. 287, 42379–42388 (2012).
Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).
Zhang, C. & Cuervo, A. M. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 14, 959–965 (2008).
Matsumoto, N. et al. Comprehensive proteomics analysis of autophagy-deficient mouse liver. Biochem. Biophys. Res. Commun. 368, 643–649 (2008).
Jain, A. et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem. 285, 22576–22591 (2010).
Lau, A. et al. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol. Cell. Biol. 30, 3275–3285 (2010).
Komatsu, M. et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12, 213–223 (2010).
Taguchi, K. et al. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc. Natl Acad. Sci. USA 109, 13561–13566 (2012).
Scherz-Shouval, R. et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26, 1749–1760 (2007).
Ogata, M. et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 26, 9220–9231 (2006).
Yorimitsu, T., Nair, U., Yang, Z. & Klionsky, D. J. Endoplasmic reticulum stress triggers autophagy. J. Biol. Chem. 281, 30299–30304 (2006).
Fuest, M. et al. The transcription factor c-Jun protects against sustained hepatic endoplasmic reticulum stress thereby promoting hepatocyte survival. Hepatology 55, 408–418 (2012).
Kouroku, Y. et al. ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 14, 230–239 (2007).
Bernales, S., Schuck, S. & Walter, P. ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3, 285–287 (2007).
Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467–478 (2010).
Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).
Lomas, D. A., Evans, D. L., Finch, J. T. & Carrell, R. W. The mechanism of Z α1-antitrypsin accumulation in the liver. Nature 357, 605–607 (1992).
Perlmutter, D. H. & Silverman, G. A. Hepatic fibrosis and carcinogenesis in alpha1-antitrypsin deficiency: a prototype for chronic tissue damage in gain-of-function disorders. Cold Spring Harb. Perspect. Biol. 3 (2011).
Kamimoto, T. et al. Intracellular inclusions containing mutant α1-antitrypsin Z are propagated in the absence of autophagic activity. J. Biol. Chem. 281, 4467–4476 (2006).
Qu, D., Teckman, J. H., Omura, S. & Perlmutter, D. H. Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J. Biol. Chem. 271, 22791–22795 (1996).
Teckman, J. H., An, J. K., Loethen, S. & Perlmutter, D. H. Fasting in alpha1-antitrypsin deficient liver: consultative activation of autophagy. Am. J. Physiol. 283, G1156–G1165 (2002).
Hidvegi, T. et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 329, 229–232 (2010).
US National Library of Medicine. ClinicalTrials.gov[online], (2013).
Pastore, N. et al. Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in α-1-anti-trypsin deficiency. EMBO Mol. Med. 5, 397–412 (2013).
Harada, M. Autophagy is involved in the elimination of intracellular inclusions, Mallory-Denk bodies, in hepatocytes. Med. Mol. Morphol. 43, 13–18 (2010).
Domart, M. C. et al. Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy. J. Hepatol. 51, 881–889 (2009).
Lu, Z. et al. Participation of autophagy in the degeneration process of rat hepatocytes after transplantation following prolonged cold preservation. Arch. Histol. Cytol. 68, 71–80 (2005).
Kim, J. S. et al. Impaired autophagy: a mechanism of mitochondrial dysfunction in anoxic rat hepatocytes. Hepatology 47, 1725–1736 (2008).
Gotoh, K. et al. Participation of autophagy in the initiation of graft dysfunction after rat liver transplantation. Autophagy 5, 351–360 (2009).
Fang, H., Liu, A., Dahmen, U. & Dirsch, O. Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase. Cell Death Dis. 4, e694 (2013).
Padrissa-Altes, S., Zaouali, M. A., Bartrons, R. & Rosello-Catafau, J. Ubiquitin-proteasome system inhibitors and AMPK regulation in hepatic cold ischaemia and reperfusion injury: possible mechanisms. Clin. Sci. (Lond.) 123, 93–98 (2012).
Zaouali, M. A. et al. AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation: a role for melatonin and trimetazidine cocktail. J. Pineal. Res. 55, 65–78 (2013).
Evankovich, J. et al. Calcium/calmodulin-dependent protein kinase IV limits organ damage in hepatic ischemia-reperfusion injury through induction of autophagy. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G189–G198 (2012).
Liu, A., Fang, H., Dahmen, U. & Dirsch, O. Chronic lithium treatment protects against liver ischemia/reperfusion injury in rats. Liver Transpl. 19, 762–772 (2013).
Degli Esposti, D. et al. Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes. Cell Death Dis. 2, e111 (2011).
Wang, J. H. et al. Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice. Gastroenterology 141, 2188–2199.e6 (2011).
Wang, D. et al. The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice. Autophagy 8, 954–962 (2012).
Sun, K. et al. Autophagy lessens ischemic liver injury by reducing oxidative damage. Cell Biosci. 3, 26 (2013).
Kovacs, A. L. & Seglen, P. O. Inhibition of hepatocytic protein degradation by inducers of autophagosome accumulation. Acta Biol. Med. Ger. 41, 125–130 (1982).
Ding, W. X., Li, M. & Yin, X. M. Selective taste of ethanol-induced autophagy for mitochondria and lipid droplets. Autophagy 7, 248–249 (2011).
Noh, B. K. et al. Restoration of autophagy by puerarin in ethanol-treated hepatocytes via the activation of AMP-activated protein kinase. Biochem. Biophys. Res. Commun. 414, 361–366 (2011).
Yang, L., Wu, D., Wang, X. & Cederbaum, A. I. Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver. Free Radic. Biol. Med. 53, 1170–1180 (2012).
Thomes, P. G. et al. Proteasome activity and autophagosome content in liver are reciprocally regulated by ethanol treatment. Biochem. Biophys. Res. Commun. 417, 262–267 (2012).
Thomes, P. G. et al. Multilevel regulation of autophagosome content by ethanol oxidation in HepG2 cells. Autophagy 9, 63–73 (2013).
Sid, B., Verrax, J. & Calderon, P. B. Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease. Biochem. Pharmacol. 86, 200–209 (2013).
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. 402, 116–122 (2010).
Ni, H. M., Bockus, A., Boggess, N., Jaeschke, H. & Ding, W. X. Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 55, 222–232 (2012).
Koliaki, C. & Roden, M. Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease. Mol. Cell. Endocrinol. 379, 35–42 (2013).
Cui, M., Yu, H., Wang, J., Gao, 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, 852754 (2013).
Koga, H., Kaushik, S. & Cuervo, A. M. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 24, 3052–3065 (2010).
Liu, H. Y. et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J. Biol. Chem. 284, 31484–31492 (2009).
Cuervo, A. M. & Dice, J. F. Age-related decline in chaperone-mediated autophagy. J. Biol. Chem. 275, 31505–31513 (2000).
Rodriguez-Navarro, J. A. et al. Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc. Natl Acad. Sci. USA 109, E705–E714 (2012).
Lin, C. W. et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J. Hepatol. 58, 993–999 (2013).
Levine, B., Mizushima, N. & Virgin, H. W. Autophagy in immunity and inflammation. Nature 469, 323–335 (2011).
Deretic, V. Autophagy in immunity and cell-autonomous defense against intracellular microbes. Immunol. Rev. 240, 92–104 (2011).
Sir, D. & Ou, J. H. Autophagy in viral replication and pathogenesis. Mol. Cells 29, 1–7 (2010).
Orvedahl, A. et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23–35 (2007).
Kyei, G. B. et al. Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J. Cell. Biol. 186, 255–268 (2009).
Kudchodkar, S. B. & Levine, B. Viruses and autophagy. Rev. Med. Virol. 19, 359–378 (2009).
Rautou, P. E. et al. Autophagy in liver diseases. J. Hepatol. 53, 1123–1134 (2010).
Sir, D. et al. The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc. Natl Acad. Sci. USA 107, 4383–4388 (2010).
Li, J. et al. Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J. Virol. 85, 6319–6333 (2011).
Tian, Y., Sir, D., Kuo, C. F., Ann, D. K. & Ou, J. H. Autophagy required for hepatitis B virus replication in transgenic mice. J. Virol. 85, 13453–13456 (2011).
Tang, H. et al. Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression. Hepatology 49, 60–71 (2009).
Rosen, H. R. Clinical practice. Chronic hepatitis C infection. N. Engl. J. Med. 364, 2429–2438 (2011).
Ait-Goughoulte, M. et al. Hepatitis C virus genotype 1a growth and induction of autophagy. J. Virol. 82, 2241–2249 (2008).
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 106, 14046–14051 (2009).
Sir, D. et al. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology 48, 1054–1061 (2008).
Su, W. C. et al. Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J. Virol. 85, 10561–10571 (2011).
Shrivastava, S., Bhanja Chowdhury, J., Steele, R., Ray, R. & Ray, R. B. Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J. Virol. 86, 8705–8712 (2012).
Kim, S. J., Syed, G. H. & Siddiqui, A. Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy. PLoS Pathog. 9, e1003285 (2013).
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. 121, 37–56 (2011).
Taguwa, S. et al. Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating hepatitis C virus. J. Virol. 85, 13185–13194 (2011).
Gosert, R. et al. Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. J. Virol. 77, 5487–5492 (2003).
Guevin, C. et al. Autophagy protein ATG5 interacts transiently with the hepatitis C virus RNA polymerase (NS5B) early during infection. Virology 405, 1–7 (2010).
McLauchlan, J. Lipid droplets and hepatitis C virus infection. Biochim. Biophys. Acta 1791, 552–559 (2009).
Shrivastava, S., Raychoudhuri, A., Steele, R., Ray, R. & Ray, R. B. Knockdown of autophagy enhances the innate immune response in hepatitis C virus-infected hepatocytes. Hepatology 53, 406–414 (2011).
Kisen, G. O. et al. Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. Carcinogenesis 14, 2501–2505 (1993).
Mathew, R. et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 21, 1367–1381 (2007).
Liang, X. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676 (1999).
Chen, H. Y. & White, E. Role of autophagy in cancer prevention. Cancer Prev. Res. (Phila.) 4, 973–983 (2011).
Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).
White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer 12, 401–410 (2012).
Morselli, E. et al. Anti- and pro-tumor functions of autophagy. Biochim. Biophys. Acta 1793, 1524–1532 (2009).
Pfeifer, U. Inhibited autophagic degradation of cytoplasm during compensatory growth of liver cells after partial hepatectomy. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 30, 313–333 (1979).
Song, J. et al. Autophagy in hypoxia protects cancer cells against apoptosis induced by nutrient deprivation through a Beclin1-dependent way in hepatocellular carcinoma. J. Cell. Biochem. 112, 3406–3420 (2011).
Takamura, A. et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25, 795–800 (2011).
Ding, Z. B. et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res. 68, 9167–9175 (2008).
Qu, X. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).
Toshima, T. et al. Autophagy enhances hepatocellular carcinoma progression by activation of mitochondrial beta-oxidation. J. Gastroenterol. http://dx.doi.org/10.1007/s00535-013-0835-0.
Li, J. et al. Autophagy promotes hepatocellular carcinoma cell invasion through activation of epithelial-mesenchymal transition. Carcinogenesis 34, 1343–1351 (2013).
Wang, R. C. & Levine, B. Autophagy in cellular growth control. FEBS Lett. 584, 1417–1426 (2010).
Inami, Y. et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J. Cell. Biol. 193, 275–284 (2011).
Shi, Y. H. et al. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy 7, 1159–1172 (2011).
Gauthier, A. & Ho, M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol. Res. 43, 147–154 (2013).
Guo, X. L. et al. Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma. J. Mol. Med. (Berl.) 91, 473–483 (2013).
Liu, Y. L. et al. Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Autophagy 6, 1057–1065 (2010).
Decaens, T. et al. Phase II study of sirolimus in treatment-naive patients with advanced hepatocellular carcinoma. Dig. Liver Dis. 44, 610–616 (2012).
Xu, Y. et al. miR-101 inhibits autophagy and enhances cisplatin-induced apoptosis in hepatocellular carcinoma cells. Oncol. Rep. 29, 2019–2024 (2013).
Kon, M. et al. Chaperone-mediated autophagy is required for tumor growth. Sci. Transl. Med. 3, ra117 (2011).
Saha, T. LAMP2A overexpression in breast tumors promotes cancer cell survival via chaperone-mediated autophagy. Autophagy 8 (2012).
Acknowledgements
Work in the laboratory of A. M. Cuervo is supported by grants from the NIH AG21904, AG031782, DK098408, a Hirschl/Weill-Caulier Career Scientist Award and the generous support of R. and R. Belfer. J. L. Schneider is supported by NIH/NIA T32-NS007098, T32-GM007288 and F30-AG046109.
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Schneider, J., Cuervo, A. Liver autophagy: much more than just taking out the trash. Nat Rev Gastroenterol Hepatol 11, 187–200 (2014). https://doi.org/10.1038/nrgastro.2013.211
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DOI: https://doi.org/10.1038/nrgastro.2013.211
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