Cited by 311Alcohol Consumption and Health EffectsCell death mechanisms and regulationLiver physiology and pathology

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Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury

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Roychowdhury, Sanjoy, McMullen, Megan R., Pisano, Sorana G., Liu, Xiuli, Nagy, Laura E.·2013·Hepatology

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Abstract

Hepatocyte cell death via apoptosis and necrosis are major hallmarks of ethanol-induced liver injury. However, inhibition of apoptosis is not sufficient to prevent ethanol-induced hepatocyte injury or inflammation. Because receptor-interacting protein kinase (RIP) 3–mediated necroptosis, a nonapoptotic cell death pathway, is implicated in a variety of pathological conditions, we tested the hypothesis that ethanol-induced liver injury is RIP3-dependent and RIP1-independent. Increased expression of RIP3 was detected in livers of mice after chronic ethanol feeding, as well as in liver biopsies from patients with alcoholic liver disease. Chronic ethanol feeding failed to induce RIP3 in the livers of cytochrome P450 2E1 (CYP2E1)-deficient mice, indicating CYP2E1-mediated ethanol metabolism is critical for RIP3 expression in response to ethanol feeding. Mice lacking RIP3 were protected from ethanol-induced steatosis, hepatocyte injury, and expression of proinflammatory cytokines. In contrast, RIP1 expression in mouse liver remained unchanged following ethanol feeding, and inhibition of RIP1 kinase by necrostatin-1 did not attenuate ethanol-induced hepatocyte injury. Ethanol-induced apoptosis, assessed by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling–positive nuclei and accumulation of cytokeratin-18 fragments in the liver, was independent of RIP3. Conclusion : CYP2E1-dependent RIP3 expression induces hepatocyte necroptosis during ethanol feeding. Ethanol-induced hepatocyte injury is RIP3-dependent, but independent of RIP1 kinase activity; intervention of this pathway could be targeted as a potential therapeutic strategy.

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Authors: Roychowdhury, S., McMullen, M. R., Pisano, S. G., Liu, X., & Nagy, L. E.
Affiliations: Cleveland Clinic (US)
Corresponding author: Roychowdhury, Sanjoy
ORCID: Roychowdhury, Sanjoy
McMullen, Megan R.
Liu, Xiuli
Nagy, Laura E.
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2013-05
Volume: 57
Issue: 5
Pages: 1773-1783
ISSN: 0270-9139 (ISSN-L)
DOI: 10.1002/hep.26200
PMC: PMC3628968
OpenAlex: W1993485143
Cited by: 304
References: 43
Citations by year: 2026: 3 · 2025: 9 · 2024: 19 · 2023: 22 · 2022: 24 · 2021: 16 · 2020: 25 · 2019: 29 · 2018: 24 · 2017: 33 · 2016: 33 · 2015: 25 · 2014: 31 · 2013: 11
FWCI: 15.46
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 853 d)
Locations: Hepatology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: ABMRF/The Foundation for Alcohol Research
National Institutes of Health (P20 AA17069)
National Institute on Alcohol Abuse and Alcoholism (P20 AA17069, R01AA013868, R01AA011975, P20AA017837)
National Center for Research Resources (UL1RR024989)
Topics: Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords: RIPK3, RIPK1, necroptosis, ethanol-induced liver injury, alcoholic liver disease, hepatocyte apoptosis, CYP2E1, necrostatin-1, steatosis, inflammatory cytokines
MeSH terms: Adult, Ethanol, Animals, Biopsy, Disease Models, Animal, Female, Humans, Imidazoles, Indoles, Liver, Liver Diseases, Alcoholic, Male, Mice, Inbred C57BL, Middle Aged, Apoptosis, Mice, Knockout, Cytochrome P-450 CYP2E1, Hepatocytes, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Chemical and Drug Induced Liver Injury

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Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury

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