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Caspase 3 Inactivation Protects Against Hepatic Cell Death and Ameliorates Fibrogenesis in a Diet-Induced NASH Model
Open accessAbstract
Background/aims Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH). As the contribution of specific caspases remains unclear, our aim was to ascertain the effect of caspase 3 suppression on liver injury and fibrogenesis. Methods C57BL/6 wild-type (WT) and caspase 3 knock out (Casp3 (-/-)) mice were placed on a methionine- and choline-deficient (MCD) diet for 6 weeks to induce steatohepatitis and liver fibrosis. Thereafter, liver injury, liver fibrosis and hepatocellular apoptosis were quantified in liver sections. Additionally, expression of proteins associated with liver inflammation and fibrogenesis was analyzed. Results WT mice fed MCD diet showed marked activation of caspase 3 in hepatocytes, in conjunction with steatohepatitis and increased hepatic triglyceride levels, hepatocyte ballooning, inflammation and fibrosis. Casp3 (-/-) mice fed the MCD diet showed similar serum aminotransferase levels and NAFLD activity scores (NAS) compared with WT MCD-fed mice. However, Casp3 (-/-) mice on the MCD diet showed a marked reduction in expression of transcripts for profibrogenic genes, which translated into reduced hepatic collagen deposition. These changes were associated with decreased levels of apoptosis, and a significant reduction in the expression of cytokines involved in inflammatory signaling. Casp3 (-/-) mice on the MCD showed a reduction in expression of chemokine receptor 2 (CCR2) leading to ameliorated infiltration of inflammatory lymphocyte antigen 6 complex, locus C1 (Ly6c) positive monocytes. Conclusion These findings support a prominent role for hepatocyte caspase 3 activation in NASH-related apoptosis, fibrogenesis and fibrosis which in part is mediated via CCR2-dependent infiltration of Ly6c positive monocytes.
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“However, the most relevant way of dying for hepatocytes seems to be apoptosis as indicated by caspase 3 cleavage and TUNEL staining in both human MASH liver tissue and murine models(207, 208).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [208]
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Metadata
- Authors
- Thapaliya, S., Wree, A., Povero, D., Inzaugarat, M. E., Berk, M., Dixon, L., Papouchado, B. G., & Feldstein, A. E.
- Affiliations
- Cleveland Clinic (US)
- University of California San Diego (US)
- Corresponding author
- Feldstein, Ariel E.
- Venue
- Digestive Diseases and Sciences
- Published
- 2014-05-03
- Volume
- 59
- Issue
- 6
- Pages
- 1197-1206
- ISSN
- 0163-2116 (ISSN-L)
- 1573-2568
- PMC
- PMC4512760
- OpenAlex
- W2040177711
- Cited by
- 162
- References
- 42
- Citations by year
- 2026: 9 · 2025: 24 · 2024: 17 · 2023: 20 · 2022: 13 · 2021: 10 · 2020: 18 · 2019: 16 · 2018: 14 · 2017: 8 · 2016: 5 · 2015: 7 · 2014: 1
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Digestive Diseases and Sciences (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Toronto
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082451, R01DK076852, DK082451, DK-076852)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- caspase-3, nonalcoholic steatohepatitis, liver fibrosis, hepatocyte apoptosis, methionine-choline-deficient diet, CCR2, Ly6C+ monocytes, monocyte infiltration, liver inflammation, hepatic steatosis
- MeSH terms
- Animals, Antigens, Ly, Choline, Collagen, Dose-Response Relationship, Drug, Fatty Liver, Gene Expression Regulation, Liver Cirrhosis, Methionine, Mice, Inbred C57BL, Apoptosis, Mice, Knockout, Hepatocytes, Mice, Caspase 3, Receptors, CCR2, Hepatic Stellate Cells, Non-alcoholic Fatty Liver Disease
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