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Sirtuin 1 (SIRT1) Protein Degradation in Response to Persistent c-Jun N-terminal Kinase 1 (JNK1) Activation Contributes to Hepatic Steatosis in Obesity
Open accessAbstract
SIRT1 is involved in the pathogenesis of obesity, diabetes, and aging. However, it is not clear how SIRT1 activity is regulated by intracellular kinases in cells. In this study, we investigated SIRT1 phosphorylation and protein degradation in response to JNK1 activation in obese mice. Mouse SIRT1 is phosphorylated by JNK1 at Ser-46 (Ser-47 in human SIRT1), which is one of the four potential residues targeted by JNK1. The phosphorylation induces a brief activation of SIRT1 function and degradation of SIRT1 thereafter by the proteasome. Ubiquitination occurs in SIRT1 protein after the phosphorylation. Mutation of Ser-46 to alanine prevents the phosphorylation, ubiquitination, and degradation. In vivo, SIRT1 undergoes an extensive degradation in hepatocytes in obesity as a consequence of persistent activation of JNK1. The degradation leads to inhibition of SIRT1 function, which contributes to development of hepatic steatosis. The degradation disappears in obesity when JNK1 is inactivated in mice. JNK2 exhibits an opposite activity in the regulation of SIRT1 degradation. The JNK1-SIRT1 pathway provides a new molecular mechanism for the pathogenesis of hepatic steatosis in obesity.
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“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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Metadata
- Authors
- Gao, Z., Zhang, J., Kheterpal, I., Kennedy, N., Davis, R. J., & Ye, J.
- Affiliations
- Pennington Biomedical Research Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Ye, Jianping
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 286
- Issue
- 25
- Pages
- 22227-22234
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3121368
- OpenAlex
- W2001428385
- Cited by
- 187
- References
- 46
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 6 · 2021: 15 · 2020: 12 · 2019: 15 · 2018: 16 · 2017: 16 · 2016: 17 · 2015: 20 · 2014: 13 · 2013: 21 · 2012: 13
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institutes of Health (DK085495)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-085495, R56DK068036, R01DK085495, R01DK068036, DK068036, P30DK072476)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- SIRT1, JNK1, JNK2, protein degradation, ubiquitination, proteasome, hepatic steatosis, obesity, hepatocytes
- MeSH terms
- Animals, Cell Line, Dietary Fats, Enzyme Activation, Fatty Liver, Histone Deacetylases, Humans, Male, Mice, Inbred C57BL, Obesity, Phosphorylation, Mitogen-Activated Protein Kinase 8, Mice, Rats, Ubiquitination, Gene Knockout Techniques, Sirtuin 1
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