Cited by 162Liver Disease Diagnosis and TreatmentLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

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Caspase 3 Inactivation Protects Against Hepatic Cell Death and Ameliorates Fibrogenesis in a Diet-Induced NASH Model

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Thapaliya, Samjhana, Wree, Alexander, Povero, Davide, Inzaugarat, Maria Eugenia, Berk, Michael, Dixon, Laura, Papouchado, Bettina G., Feldstein, Ariel E.·2014·Digestive Diseases and Sciences

DOI 10.1007/s10620-014-3167-6PMC PMC4512760

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Abstract

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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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.
ORCID: Thapaliya, Samjhana
Wree, Alexander
Povero, Davide
Berk, Michael
Feldstein, Ariel E.
Venue: Digestive Diseases and Sciences
Publisher: Springer Science and Business Media LLC
Published: 2014-05-03
Volume: 59
Issue: 6
Pages: 1197-1206
ISSN: 0163-2116 (ISSN-L)
1573-2568
DOI: 10.1007/s10620-014-3167-6
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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Caspase 3 Inactivation Protects Against Hepatic Cell Death and Ameliorates Fibrogenesis in a Diet-Induced NASH Model

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