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Liver Diseases pp 37–52Cite as

Hepatocellular Death: Apoptosis, Autophagy, Necrosis and Necroptosis

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Abstract

Without a doubt, hepatocellular death exists in all types of human liver disease such as viral, metabolic, autoimmune and toxic conditions. Presently, the recommendations of the Nomenclature Committee on Cell Death 2018 are grading cell death into three morphotypes apoptosis, autophagy and necrosis. Apoptosis and necrosis represent two major modes of hepatocyte death, and apoptosis assures tissue homeostasis by the physiologic removal of damaged hepatocytes. Signaling death pathways of liver might carry significant findings for a correct treatment of hepatic disorders. Lastly, upcoming studies should reveal knowledge regarding the liver regulation of hepatic signaling death pathways. A comprising overview of hepatocyte death is developed in this chapter.

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Abbreviations

AIF:

Apoptosis-inducing factor

ALD:

Alcoholic liver disease

AP-1:

Activator protein-1

AP-1:

The activation protein-1

APAF-1:

Apoptosis protease-activating factor-1

Atg:

Autophagy-related proteins

ATP:

Adenosine triphosphate

ATP:

Deoxyadenosine triphosphate

Bcl-2:

(B-cell lymphoma-2)

c-FLIP:

Cellular FLICE-like inhibitory protein

DAMPs:

Damage-associated molecular patterns

DISC:

The death-inducing signaling complex

FADD:

Fas-associated protein with a death domain

FasL:

Fas Ligand

HMGB1:

Protein (high-mobility group box-1) or HMG-1 (high—mobility group)1

Hsc70:

The chaperone heat shock cognate 70

IAP:

Inhibitors of apoptotic proteins

IKK complex:

I-kappa B kinase complex

JNK:

c-Jun N-terminal kinase

LAMP2A:

Lysosome-associated membrane protein 2A

LUBAC:

Linear ubiquitin chain assembly complex

MAPK:

Mitogen-activated protein kinase

MAPK:

Mitogen-activated protein kinases

MLKL:

Mixed-lineage kinase domain-like

MOMP:

Mitochondrial outer membrane permeabilization

MOMP:

Mitochondrial outer membrane permeabilization

mTOR kinase:

The mammalian target of rapamycin kinase

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

NF-KB:

Transcription factor nuclear factor

PCD:

Programmed cell death

PI3K:

Class III phosphatidyl inositol-3 kinase

PRRs:

The pathogen recognition receptors

PS:

Phosphatidylserine

RIPK:

Receptor interacting protein kinase or receptor interacting serine-threonine kinase

RIPs:

Receptor interacting proteins

ROS:

Reactive oxygen species

Smac:

Second activator of mitochondrial apoptosis

TFEB:

Transcription factor EB

TGF-β1:

Transforming growth factor

TNF:

Tumor necrosis factor

TNFR1:

TNF receptor type 1

TNFR2:

TNF receptor type

TNF-α:

Tumor necrosis factor

TRADD:

TNF receptor associated death domain protein

TRAF2:

TNF receptor-associated factor 2

TRAIL:

TNF related apoptosis-inducing ligand

TRAIL:

TNF-released apoptosis-inducing ligand

TRAIL-R:

TNF-related apoptosis-inducing ligand receptor

UTP:

Uridine triphosphate

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Author information

Authors and Affiliations

  1. Department of Gastroenterology, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Florentina Radu-Ionita

  2. Internal Medicine Department, Faculty of Medicine, “Titu Maiorescu” University, Bucharest, Romania

    Florentina Radu-Ionita & Ion C. Tintoiu

  3. “Prof. C.C. Iliescu” Emergency Institute for Cardiovascular Diseases, Bucharest, Romania

    Ecaterina Bontas

  4. Cardiology Department, “Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania

    Ion C. Tintoiu

Authors
  1. Florentina Radu-Ionita
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  2. Ecaterina Bontas
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  3. Ion C. Tintoiu
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Editor information

Editors and Affiliations

  1. Faculty of Medicine, “Titu Maiorescu” University, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Florentina Radu-Ionita

  2. New Jersey Medical School, Rutgers University New Jersey Medical School, Newark, NJ, USA

    Nikolaos T. Pyrsopoulos

  3. Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Mariana Jinga

  4. Faculty of Medicine, “Titu Maiorescu” University, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania

    Ion C. Tintoiu

  5. Medical Radiation Sciences, Curtin University, Perth, WA, Australia

    Zhonghua Sun

  6. “Prof. C.C. Iliescu” Emergency Institute for Cardiovascular Diseases, Bucharest, Romania

    Ecaterina Bontas

Self Study

Self Study

1.1 Questions

  1. 1.

    Which statement is true?

    1. (a)

      Cell death is grading into four morphotypes apoptosis, autophagy, necrosis and necroptosis.

    2. (b)

      Apoptosis is morphologically defined by a smaller spheric cell with plasma membrane blebbing.

    3. (c)

      Extrinsic apoptosis as a form of incidental cell death.

    4. (d)

      p53 is blocked by damaged DNA.

  2. 2.

    Which statement/statements is/are true?

    1. (a)

      Mitochondrial dysfunction is a feature for both apoptosis and necrosis.

    2. (b)

      Apoptosis is a feature of cholestasis, alcoholic hepatitis, non-alcoholic steatohepatitis, autoimmune hepatitis, viral hepatitis, fulminate hepatic failure, ischemia-reperfusion injury, fibrosis and cirrhosis.

    3. (c)

      DAMPs have low release in apoptosis, necrosis and necroptosis.

    4. (d)

      Extracellular cytochrome c activates apoptosome formation.

1.2 Answers

  1. 1.

    Which statement is true?

    1. (a)

      Cell death is grading into three morphotypes apoptosis, autophagy and necrosis.

    2. (b)

      Hepatocyte apoptosis is morphologically defined by a smaller spheric cell, reduction of cell or ‘’cell shrinkage”, plasma membrane blebbing, chromatin condensation (pyknosis or small pyknotic nucleus), nuclear fragmentation (karyorrhexis), DNA splitting, mitochondrial permeabilization, cytoplasmic condensation (hypereosinophilic cytoplasm), followed by cell fragmentation into apoptotic bodies that are removed within lysosomes. Note: chromatin condensation is a hallmark of apoptosis CORRECT.

    3. (c)

      Extrinsic apoptosis as a form of regulated cell death induced or triggered by perturbations of the extracellular microenvironment that are detected by plasma membrane receptors, propagated by caspase-8 (with the optional involvement of MOMP), and precipitated by executioner caspases, mainly caspase-3.

    4. (d)

      p53 named the ‘’guardian of genome” is another intracellular regulator that decides if damaged DNA from undergoing apoptosis may be removed or repaired. As such, p53 is triggered by damaged DNA, ischemia, oxidative stress, hypoxia and heat shock.

  2. 2.

    Which statement/statements is/are true?

    1. (a)

      Mitochondrial dysfunction is a significant feature for both apoptosis and necrosis but with different molecular mechanisms. CORRECT.

    2. (b)

      There is an increased apoptosis in cholestasis, alcoholic hepatitis, non-alcoholic steatohepatitis, autoimmune hepatitis, viral hepatitis, fulminate hepatic failure, ischemia-reperfusion injury, fibrosis and cirrhosis. In case of hepatitis, apoptosis is the major cell death, being a cytoprotective mechanism in the liver clearance from infections. CORRECT.

    3. (c)

      The reduced inflammatory response of apoptosis is caused by decreased discharge of DAMPs (Damage-associated molecular patterns) and rapid exclusion of apoptotic bodies. However, the mainly discharge of DAMPs appears in necrosis and necroptosis.

    4. (d)

      Mitochondrial cytochrome c activates apoptosome formation that is a complex containing cytochrome c, APAF-1 (apoptosis protease-activating factor-1), ATP and procaspases-9. Caspase 9 activates further caspase 3.

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Radu-Ionita, F., Bontas, E., Tintoiu, I.C. (2020). Hepatocellular Death: Apoptosis, Autophagy, Necrosis and Necroptosis. In: Radu-Ionita, F., Pyrsopoulos, N., Jinga, M., Tintoiu, I., Sun, Z., Bontas, E. (eds) Liver Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-24432-3_4

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  • DOI: https://doi.org/10.1007/978-3-030-24432-3_4

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-24431-6

  • Online ISBN: 978-3-030-24432-3

  • eBook Packages: MedicineMedicine (R0)

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