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Cited by 477Cell death mechanisms and regulationLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

Hepatocyte Death: A Clear and Present Danger

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Malhi, Harmeet, Guicciardi, Maria Eugenia, Gores, Gregory J.·2010·Physiological Reviews
DOI 10.1152/physrev.00061.2009PMC PMC2943859
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Abstract

The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolism including drugs and alcohol, participation in lipid and fatty acid metabolism, its unique role in the enterohepatic circulation of bile acids, the widespread prevalence of hepatotropic viruses, and its existence within a milieu of innate immune responding cells. Apoptosis and necrosis are the most widely recognized forms of hepatocyte cell death. The hepatocyte displays many unique features regarding cell death by apoptosis. It is quite susceptible to death receptor-mediated injury, and its death receptor signaling pathways involve the mitochondrial pathway for efficient cell killing. Also, death receptors can trigger lysosomal disruption in hepatocytes which further promote cell and tissue injury. Interestingly, hepatocytes are protected from cell death by only two anti-apoptotic proteins, Bcl-x(L) and Mcl-1, which have nonredundant functions. Endoplasmic reticulum stress or the unfolded protein response contributes to hepatocyte cell death during alterations of lipid and fatty acid metabolism. Finally, the current information implicating RIP kinases in necrosis provides an approach to more fully address this mode of cell death in hepatocyte injury. All of these processes contributing to hepatocyte injury are discussed in the context of potential therapeutic strategies.

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  • Excessive lipid accumulation in hepatocytes results in massive hepatocyte death, which triggers pro-inflammatory and pro-fibrogenic responses, increasing the risk of liver cancer.

    “Excessive lipid accumulation in hepatocytes results in massive hepatocyte death, which triggers pro-inflammatory and pro-fibrogenic responses, increasing the risk of liver cancer [44].”

    From Pathophysiological Aspects of Alcohol Metabolism in the Liver (2021) · cites this paper as [44]

    Section III.A links excess free fatty acids to increased hepatocyte apoptosis in NASH, while Section II.A links hepatocyte apoptosis to inflammation, fibrosis, and conditions permissive for liver cancer (page numbers unavailable). The claim overstates this as massive death caused by lipid accumulation generally: the paper distinguishes toxic free fatty acids from stored triglycerides and does not establish that magnitude of cell death. (LLM, conf=0.88)

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Authors
Malhi, H., Guicciardi, M. E., & Gores, G. J.
Affiliations
Mayo Clinic (US)
Corresponding author
Gores, Gregory J.
ORCID
Venue
Physiological Reviews
Publisher
American Physiological Society
Published
2010-07
Volume
90
Issue
3
Pages
1165-1194
ISSN
  • 0031-9333 (ISSN-L)
  • 1522-1210
DOI
10.1152/physrev.00061.2009
PMC
PMC2943859
OpenAlex
W2004981017
Cited by
477
References
23
Citations by year
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FWCI
2.50
Type
journal article
Language
en
Open access
Locations
  • Physiological Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK63947, T32 DK-07198-34, R01DK063947, R01-DK41876, R37DK041876, R01DK041876, T32DK007198)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
hepatocyte death, apoptosis, necrosis, death receptors, mitochondrial apoptosis, lysosomal disruption, Bcl-xL, Mcl-1, endoplasmic reticulum stress, unfolded protein response, fatty acid metabolism, RIP kinases, hepatotoxicity, drug-induced liver injury, bile acid enterohepatic circulation, hepatotropic viruses, anti-apoptotic proteins
MeSH terms
Animals, Autophagy, Endoplasmic Reticulum, Humans, Liver Diseases, Mitochondria, Necrosis, Stress, Physiological, Signal Transduction, Apoptosis, Hepatocytes, Apoptosis Regulatory Proteins, Receptors, Death Domain, Unfolded Protein Response

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