JNK1 but not JNK2 promotes the development of steatohepatitis in mice
Open accessAbstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and varying degrees of necroinflammation. Although chronic oxidative stress, inflammatory cytokines, and insulin resistance have been implicated in the pathogenesis of NAFLD, the mechanisms that underlie the initiation and progression of this disease remain unknown. c-Jun N-terminal kinase (JNK) is activated by oxidants and cytokines and regulates hepatocellular injury and insulin resistance, suggesting that this kinase may mediate the development of steatohepatitis. The presence and function of JNK activation were therefore examined in the murine methionine- and choline-deficient (MCD) diet model of steatohepatitis. Activation of hepatic JNK, c-Jun, and AP-1 signaling occurred in parallel with the development of steatohepatitis in MCD diet-fed mice. Investigations in jnk1 and jnk2 knockout mice demonstrated that jnk1, but not jnk2, was critical for MCD diet-induced JNK activation. JNK promoted the development of steatohepatitis as MCD diet-fed jnk1 null mice had significantly reduced levels of hepatic triglyceride accumulation, inflammation, lipid peroxidation, liver injury, and apoptosis compared with wild-type and jnk2 -/- mice. Ablation of jnk1 led to an increase in serum adiponectin but had no effect on serum levels of tumor necrosis factor-alpha. In conclusion, JNK1 is responsible for JNK activation that promotes the development of steatohepatitis in the MCD diet model. These findings also provide additional support for the critical mechanistic involvement of JNK1 overactivation in conditions associated with insulin resistance and the metabolic syndrome.
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Activation of JNK is positively related to high fat diet-induced insulin resistance and metabolic syndrome.
“In addition, activation of JNK was positively related to high fat diet-induced insulin resistance and metabolic syndrome [119], [121], [122], [123].”
Persistent activation of JNK and/or p38K is positively associated with various liver diseases such as steatohepatitis and I/R injury.
“Furthermore, persistent activation of JNK and/or p38K is positively associated with various liver diseases such as steatohepatitis and I/R injury [122], [123], [124], [125], suggesting the clinical importance of JNK and p38K in human disease states, as reviewed [126].”
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“In addition, activation of JNK was positively related to high fat diet-induced insulin resistance and metabolic syndrome [119,121–123].”
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- Authors
- Schattenberg, J. M., Singh, R., Wang, Y., Lefkowitch, J. H., Rigoli, R. M., Scherer, P. E., & Czaja, M. J.
- Affiliations
- Albert Einstein College of Medicine (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Czaja, Mark J.
- Venue
- Hepatology
- Published
- 2006-01
- Volume
- 43
- Issue
- 1
- Pages
- 163-172
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2108678340
- Cited by
- 384
- References
- 43
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 14 · 2023: 11 · 2022: 11 · 2021: 10 · 2020: 18 · 2019: 11 · 2018: 14 · 2017: 21 · 2016: 18 · 2015: 20 · 2014: 29 · 2013: 24 · 2012: 26
- FWCI
- 12.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-61498, DK 55758, R01DK055758, R01DK061498)
- Topics
- Health Sciences › Medicine › Epidemiology › 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
- JNK1, JNK2, non-alcoholic fatty liver disease, steatohepatitis, methionine-choline-deficient diet, hepatic steatosis, c-Jun, AP-1 signaling, lipid peroxidation, liver inflammation, insulin resistance, adiponectin, TNF-α, apoptosis, knockout mice
- MeSH terms
- Alanine Transaminase, Animals, Choline Deficiency, Enzyme Activation, Fatty Liver, Female, Liver, Male, Methionine, Mice, Inbred C57BL, Triglycerides, Lipid Peroxidation, Apoptosis, Intercellular Adhesion Molecule-1, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Mice, Adiponectin
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