title: Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity.
abstract: 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.
authors.affiliation: Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808, USA.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Gao
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Indu
authors.initials: I
authors.lastname: Kheterpal
authors.forename: Norm
authors.initials: N
authors.lastname: Kennedy
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Jianping
authors.initials: J
authors.lastname: Ye
mesh_terms: D000818:Animals; D002460:Cell Line; D004041:Dietary Fats / Q000009:adverse effects; D004789:Enzyme Activation; D005234:Fatty Liver / Q000150:complications* / Q000201:enzymology / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000150:complications*; D010766:Phosphorylation; D051381:Rats; D056564:Sirtuin 1 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004041:Dietary Fats; D048055:Mitogen-Activated Protein Kinase 8; D056564:Sirtuin 1; D006655:Histone Deacetylases