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Regulation of Apoptosis by Bcl-2 Family Proteins in Liver Injury

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Molecules, Systems and Signaling in Liver Injury

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

Abstract

Hepatocyte apoptosis is regulated by a fine balance of Bcl-2 family proteins. All apoptotic stimuli combine to induce Bak/Bax activation, which results in mitochondrial outer membrane permeability (MOMP). Once MOMP occurs, apoptosis is initiated by the activation of downstream caspases. Therefore, the regulation of Bak/Bax activation is critical for the regulation of hepatocyte apoptosis. Bak/Bax activation is determined by the balance between anti-apoptotic Bcl-2 family proteins and BH3-only proteins. In hepatocytes, Bcl-xL and Mcl-1 cooperatively play important roles as anti-apoptotic Bcl-2 family proteins, whereas Bid, Bim and PUMA act as BH3-only proteins. The aforementioned balance applies to both physiological and pathological conditions. A lack of Bcl-xL or Mcl-1 alters this balance in favour of Bak/Bax activation, leading to apoptosis. The further ablation of Bid or Bim reverses this effect, inhibiting Bak/Bax activation and leading to the suppression of apoptosis. Bcl-xL or Mcl-1-deficient hepatocytes evade apoptosis due to deficiencies in both Bid and Bim. In this chapter, we focus on the balance between anti-apoptotic Bcl-2 family proteins and BH3-only proteins; both types of proteins serve as key regulators of Bak/Bax activation, an essential event in hepatocyte apoptosis. We also discuss the involvement of Bcl-2 family proteins in liver disease, viral and autoimmune hepatitis, steatohepatitis and hepatocellular carcinoma. The regulation of Bcl-2 family proteins is a potent method of controlling hepatocyte cell death. Therapies targeted to Bcl-2 family proteins are being developed for clinical use, particularly for patients with hepatocellular carcinoma.

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Abbreviations

ALT:

Alanine aminotransferase

BH:

BCL-2 homology

ER:

Endoplasmic reticulum

HCC:

Hepatocellular carcinoma

LPS:

Lipopolysaccharide

MOMP:

Mitochondrial outer membrane permeability

NASH:

Non-alcoholic steatohepatitis

TNF:

Tumour necrosis factor

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Hayato Hikita & Tetsuo Takehara MD, PhD

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  1. Hayato Hikita
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  2. Tetsuo Takehara MD, PhD
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Correspondence to Tetsuo Takehara MD, PhD .

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Editors and Affiliations

  1. Department of Pharmacology Toxicology and Therapy, The University of Kansas Medical Center, Kansas City, Kansas, USA

    Wen-Xing Ding

  2. Health Pathology Laboratory, Indiana University, Indianapolis, Indiana, USA

    Xiao-Ming Yin

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Hikita, H., Takehara, T. (2017). Regulation of Apoptosis by Bcl-2 Family Proteins in Liver Injury. In: Ding, WX., Yin, XM. (eds) Molecules, Systems and Signaling in Liver Injury. Cell Death in Biology and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-58106-4_5

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