Role of Apoptosis in Liver Diseases

  • Hayato Hikita
  • Tetsuo TakeharaEmail author


In the livers of patients with various chronic hepatic diseases, including viral hepatitis, alcoholic liver disease and non-alcoholic fatty liver disease, hepatocyte apoptosis is frequently detected. Hepatocyte apoptosis is regulated by pro-apoptotic and anti-apoptotic bcl-2 family proteins. Among the anti-apoptotic proteins, Bcl-xL and Mcl-1 collaborate to prevent the activation of the mitochondrial apoptotic pathway and to maintain hepatocyte homeostasis. Hepatocyte apoptosis is directly linked with the progression of liver diseases, including liver fibrogenesis and liver tumorigenesis. The regulation of hepatocyte apoptosis is one of the therapeutic strategies to prevent the progression of chronic liver diseases. In in vitro and in vivo mouse models of non-alcoholic fatty liver disease, hepatocyte autophagy is suppressed by Rubicon overexpression leading to an increase in ER stress and hepatocyte apoptosis. Rubicon inhibition ameliorates the increase in ER stress and hepatocyte apoptosis. Rubicon overexpression is also observed in the livers of patients with non-alcoholic fatty liver disease. Rubicon-targeted improvement of hepatocyte autophagy may thus be a new therapeutic strategy for patients with non-alcoholic fatty liver disease. Therefore, further mechanistic insights into how hepatocyte apoptosis is executed in patients with different chronic liver diseases may lead to the discovery of new therapeutic strategies that can suppress the progression of chronic liver diseases.


Bcl-2 family proteins Bcl-xL Mcl-1 Chronic hepatitis Oxidative stress Liver tumorigenesis Rubicon Autophagy Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis 


  1. 1.
    Hikita H, Takehara T. Regulation of apoptosis by bcl-2 family proteins in liver injury. In: Ding WX, Yin XM, editors. Molecules, systems and signaling in liver injury. Berlin: Springer; 2017. p. 53–74.Google Scholar
  2. 2.
    Veis DJ, Sorenson CM, Shutter JR, et al. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993;75:229–40.CrossRefGoogle Scholar
  3. 3.
    Hamasaki A, Sendo F, Nakayama K, et al. Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J Exp Med. 1998;188:1985–92.CrossRefGoogle Scholar
  4. 4.
    Ross AJ, Waymire KG, Moss JE, et al. Testicular degeneration in bclw-deficient mice. Nat Genet. 1998;18:251–6.CrossRefGoogle Scholar
  5. 5.
    Print CG, Loveland KL, Gibson L, et al. Apoptosis regulator bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc Natl Acad Sci U S A. 1998;95:12424–31.CrossRefGoogle Scholar
  6. 6.
    Hikita H, Takehara T, Shimizu S, et al. Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver. Hepatology. 2009;50:1217–26.CrossRefGoogle Scholar
  7. 7.
    Takehara T, Tatsumi T, Suzuki T, et al. Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses. Gastroenterology. 2004;127:1189–97.CrossRefGoogle Scholar
  8. 8.
    Hikita H, Takehara T, Kodama T, et al. BH3-only protein bid participates in the Bcl-2 network in healthy liver cells. Hepatology. 2009;50:1972–80.CrossRefGoogle Scholar
  9. 9.
    Kodama T, Hikita H, Kawaguchi T, et al. The Bcl-2 homology 3 (BH3)-only proteins Bim and Bid are functionally active and restrained by anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) family proteins in healthy liver. J Biol Chem. 2013;288(42):30009–18.CrossRefGoogle Scholar
  10. 10.
    Takehara T, Takahashi H. Suppression of Bcl-xL deamidation in human hepatocellular carcinomas. Cancer Res. 2003;63:3054–7.PubMedGoogle Scholar
  11. 11.
    Hikita H, Kodama T, Tanaka S, et al. Activation of the mitochondrial apoptotic pathway produces reactive oxygen species and oxidative damage in hepatocytes that contribute to liver tumorigenesis. Cancer Prev Res (Phila). 2015;8:693–701.CrossRefGoogle Scholar
  12. 12.
    Hikita H, Kodama T, Shimizu S, et al. Bak deficiency inhibits liver carcinogenesis: a causal link between apoptosis and carcinogenesis. J Hepatol. 2012;57:92–100.CrossRefGoogle Scholar
  13. 13.
    Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125:437–43.CrossRefGoogle Scholar
  14. 14.
    Ratziu V, Sheikh MY, Sanyal AJ, et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology. 2012;55:419–28.CrossRefGoogle Scholar
  15. 15.
    Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68:280–95.CrossRefGoogle Scholar
  16. 16.
    Win S, Than TA, Zhang J, et al. New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases. Hepatology. 2017;67(5):2013–24.CrossRefGoogle Scholar
  17. 17.
    Povero D, Feldstein AE. Novel molecular mechanisms in the development of non-alcoholic steatohepatitis. Diabetes Metab J. 2016;40(1):11.CrossRefGoogle Scholar
  18. 18.
    Tanaka S, Hikita H, Tatsumi T, et al. Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease. Hepatology. 2016;64(6):1994–2014.CrossRefGoogle Scholar
  19. 19.
    Matsunaga K, Saitoh T, Tabata K, et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol. 2009;11:385–96.CrossRefGoogle Scholar
  20. 20.
    Zhong Y, Wang QJ, Li X, et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol. 2009;11:468–76.CrossRefGoogle Scholar
  21. 21.
    Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism. Nature. 2009;458:1131–5.CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Osaka University, Graduate School of MedicineSuitaJapan

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