Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2011-06-24Keywords
AnimalsCell Line
Dietary Fats
Enzyme Activation
Fatty Liver
Gene Knockout Techniques
Histone Deacetylases
Humans
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 8
Obesity
Phosphorylation
Rats
Sirtuin 1
Ubiquitination
Biochemistry
Cell Biology
Cellular and Molecular Physiology
Molecular Biology
Metadata
Show full item recordAbstract
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.Source
J Biol Chem. 2011 Jun 24;286(25):22227-34. doi: 10.1074/jbc.M111.228874. Epub 2011 May 3. Link to article on publisher's siteDOI
10.1074/jbc.M111.228874Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28307PubMed ID
21540183Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M111.228874