• Ying-Hong Shi
  • Jia Fan
  • Chih-Wen Lin
  • Wen-Xing Ding
  • Xiao-Ming Yin
Part of the Molecular Pathology Library book series (MPLB, volume 5)


Two major intracellular degradation systems have been defined: the ubiquitin–proteasome system and the autophagy–lysosome system. Degradation of ubiquitin-conjugated proteins is mediated by proteolysis in the proteasome. However, autophagic degradation of intracellular components is mediated by the lysosome. There are three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy, which differ in their physiological functions and in the way the cytoplasmic materials are delivered to the lysosomes [1]. Macroautophagy is an evolutionarily conserved and perhaps quantitatively most important autophagy process, in which macromolecules and subcellular organelles are delivered to the lysosomes via a vesicular structure, called autophagosome. This chapter will focus on the role of macroautophagy (hereafter referred to as autophagy) in the pathobiology of the liver.


Endoplasmic Reticulum Stress Protein Quality Control Autophagic Degradation Connective Tissue Matrix Amino Acid Deprivation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Yin XM, Ding WX, Gao W. Autophagy in the liver. Hepatology. 2008;47(5):1773–85.PubMedCrossRefGoogle Scholar
  2. 2.
    Clark Jr SL. Cellular differentiation in the kidneys of newborn mice studies with the electron microscope. J Biophys Biochem Cytol. 1957;3(3):349–62.PubMedCrossRefGoogle Scholar
  3. 3.
    De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Meijer AJ, Codogno P. Autophagy: regulation and role in disease. Crit Rev Clin Lab Sci. 2009;46(4):210–40.PubMedCrossRefGoogle Scholar
  5. 5.
    Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290(5497):1717–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Reggiori F, Klionsky DJ. Autophagosomes: biogenesis from scratch? Curr Opin Cell Biol. 2005;17(4):415–22.PubMedCrossRefGoogle Scholar
  7. 7.
    Uchiyama Y, Shibata M, Koike M, Yoshimura K, Sasaki M. Autophagy-physiology and pathophysiology. Histochem Cell Biol. 2008;129(4):407–20.PubMedCrossRefGoogle Scholar
  8. 8.
    Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 2008;4(2):151–75.PubMedGoogle Scholar
  9. 9.
    Ding WX, Yin XM. Analyzing macroautophagy in hepatocytes and the liver. Methods Enzymol. 2009;453:397–416.PubMedCrossRefGoogle Scholar
  10. 10.
    Kabeya Y, Kawamata T, Suzuki K, Ohsumi Y. Cis1/Atg31 is required for autophagosome formation in Saccharomyces cerevisiae. Biochem Biophys Res Commun. 2007;356(2):405–10.PubMedCrossRefGoogle Scholar
  11. 11.
    Klionsky DJ, Cregg JM, Dunn Jr WA, et al. A unified nomenclature for yeast autophagy-related genes. Dev Cell. 2003;5(4):539–45.PubMedCrossRefGoogle Scholar
  12. 12.
    Kamada Y, Funakoshi T, Shintani T, et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol. 2000;150(6):1507–13.PubMedCrossRefGoogle Scholar
  13. 13.
    Hosokawa N, Hara T, Kaizuka T, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009;20(7):1981–91.PubMedCrossRefGoogle Scholar
  14. 14.
    Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol. 2009;22:8.Google Scholar
  15. 15.
    Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell. 2008;19(12):5360–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Sun Q, Fan W, Chen K, et al. Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 2008;105(49):19211–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Liang C, Feng P, Ku B, et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol. 2006;8(7):688–99.PubMedCrossRefGoogle Scholar
  18. 18.
    Ohsumi Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol. 2001;2(3):211–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19(21):5720–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Liang J, Shao SH, Xu ZX, et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol. 2007;9(2):218–24.PubMedCrossRefGoogle Scholar
  21. 21.
    Kadowaki M, Kanazawa T. Amino acids as regulators of proteolysis. J Nutr. 2003;133(6 Suppl 1):2052S–6S.PubMedGoogle Scholar
  22. 22.
    Mortimore GE, Poso AR. Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu Rev Nutr. 1987;7:539–64.PubMedCrossRefGoogle Scholar
  23. 23.
    Mortimore GE, Wert Jr JJ, Miotto G, Venerando R, Kadowaki M. Leucine-specific binding of photoreactive Leu7-MAP to a high molecular weight protein on the plasma membrane of the isolated rat hepatocyte. Biochem Biophys Res Commun. 1994;203(1):200–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem. 1995;270(5):2320–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Gohla A, Klement K, Piekorz RP, et al. An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver. Proc Natl Acad Sci U S A. 2007;104(8):3003–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Ashford TP, Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol. 1962;12:198–202.PubMedCrossRefGoogle Scholar
  27. 27.
    Kotoulas OB, Kalamidas SA, Kondomerkos DJ. Glycogen autophagy. Microsc Res Tech. 2004;64(1):10–20.PubMedCrossRefGoogle Scholar
  28. 28.
    Kotoulas OB, Kalamidas SA, Kondomerkos DJ. Glycogen autophagy in glucose homeostasis. Pathol Res Pract. 2006;202(9):631–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Kotoulas OB, Phillips MJ. Fine structural aspects of the mobilization of hepatic glycogen. I. Acceleration of glycogen breakdown. Am J Pathol. 1971;63(1):1–22.PubMedGoogle Scholar
  30. 30.
    Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–45.PubMedCrossRefGoogle Scholar
  31. 31.
    Zechner R, Madeo F. Cell biology: another way to get rid of fat. Nature. 2009;458(7242):1118–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Weidberg H, Shvets E, Elazar Z. Lipophagy: selective catabolism designed for lipids. Dev Cell. 2009;16(5):628–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism. Nature. 2009;458(7242):1131–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Shibata M, Yoshimura K, Furuya N, et al. The MAP1-LC3 conjugation system is involved in lipid droplet formation. Biochem Biophys Res Commun. 2009;382(2):419–23.PubMedCrossRefGoogle Scholar
  35. 35.
    Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 2005;169(3):425–34.PubMedCrossRefGoogle Scholar
  36. 36.
    Perlmutter DH. The role of autophagy in alpha-1-antitrypsin deficiency: a specific cellular response in genetic diseases associated with aggregation-prone proteins. Autophagy. 2006;2(4):258–63.PubMedGoogle Scholar
  37. 37.
    Sveger T, Eriksson S. The liver in adolescents with alpha 1-antitrypsin deficiency. Hepatology. 1995;22(2):514–7.PubMedGoogle Scholar
  38. 38.
    Teckman JH, An JK, Loethen S, Perlmutter DH. Fasting in alpha1-antitrypsin deficient liver: constitutive [correction of consultative] activation of autophagy. Am J Physiol Gastrointest Liver Physiol. 2002;283(5):G1156–65.PubMedGoogle Scholar
  39. 39.
    Kruse KB, Brodsky JL, McCracken AA. Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human alpha-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ. Mol Biol Cell. 2006;17(1):203–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Perlmutter DH. Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in alpha-1-antitrypsin deficiency. Cell Death Differ. 2009;16(1):39–45.PubMedCrossRefGoogle Scholar
  41. 41.
    Kruse KB, Dear A, Kaltenbrun ER, et al. Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. Am J Pathol. 2006;168(4):1299–308; quiz 1404–295.Google Scholar
  42. 42.
    Ding WX, Ni HM, Gao W, et al. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol. 2007;171(2):513–24.PubMedCrossRefGoogle Scholar
  43. 43.
    Ding WX, Yin XM. Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy. 2008;4(2):141–50.PubMedGoogle Scholar
  44. 44.
    Poso AR, Surmacz CA, Mortimore GE. Inhibition of intracellular protein degradation by ethanol in perfused rat liver. Biochem J. 1987;242(2):459–64.PubMedGoogle Scholar
  45. 45.
    Donohue Jr TM. Autophagy and ethanol-induced liver injury. World J Gastroenterol. 2009;15(10):1178–85.PubMedCrossRefGoogle Scholar
  46. 46.
    Donohue Jr TM, McVicker DL, Kharbanda KK, Chaisson ML, Zetterman RK. Ethanol administration alters the proteolytic activity of hepatic lysosomes. Alcohol Clin Exp Res. 1994;18(3):536–41.PubMedCrossRefGoogle Scholar
  47. 47.
    Smith SL, Jennett RB, Sorrell MF, Tuma DJ. Acetaldehyde substoichiometrically inhibits bovine neurotubulin polymerization. J Clin Invest. 1989;84(1):337–41.PubMedCrossRefGoogle Scholar
  48. 48.
    Bernal CA, Vazquez JA, Adibi SA. Leucine metabolism during chronic ethanol consumption. Metabolism. 1993;42(9):1084–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Kondo Y, Kondo S. Autophagy and cancer therapy. Autophagy. 2006;2(2):85–90.PubMedGoogle Scholar
  50. 50.
    Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112(12):1809–20.PubMedGoogle Scholar
  51. 51.
    Levine B, Sinha S, Kroemer G. Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy. 2008;4(5):600–6.PubMedGoogle Scholar
  52. 52.
    Levine B, Abrams J. p53: the Janus of autophagy? Nat Cell Biol. 2008;10(6):637–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Ding ZB, Shi YH, Zhou J, et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res. 2008;68(22):9167–75.PubMedCrossRefGoogle Scholar
  54. 54.
    Shi YH, Ding ZB, Zhou J, Qiu SJ, Fan J. Prognostic significance of Beclin 1-dependent apoptotic activity in hepatocellular carcinoma. Autophagy. 2009;5(3):380–2.PubMedCrossRefGoogle Scholar
  55. 55.
    Bursch W, Karwan A, Mayer M, et al. Cell death and autophagy: cytokines, drugs, and nutritional factors. Toxicology. 2008;254(3):147–57.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ying-Hong Shi
    • 1
  • Jia Fan
  • Chih-Wen Lin
  • Wen-Xing Ding
  • Xiao-Ming Yin
  1. 1.Department of Liver SurgeryLiver Cancer InstituteShanghaiP.R. China

Personalised recommendations