The phosphorylation status of T522 modulates tissue‐specific functions of SIRT1 in energy metabolism in mice. (31st March 2017)

• Record Type: Journal Article
• Authors: Lu, Jing; Xu, Qing; Ji, Ming; Guo, Xiumei; Xu, Xiaojiang; Fargo, David C; Li, Xiaoling
• Is Part Of: EMBO reports. Volume 18:Number 5(2017)
• Page Start: 841
• Page End: 857
• Publication Date: 2017-03-31
• Subjects: adipogenesis -- hepatic steatosis -- liver damage -- phosphorylation -- SIRT1; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201643803
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: SIRT1, the most conserved mammalian NAD + ‐dependent protein deacetylase, is an important metabolic regulator. However, the mechanisms by which SIRT1 is regulated in vivo remain unclear. Here, we report that phosphorylation modification of T522 on SIRT1 is crucial for tissue‐specific regulation of SIRT1 activity in mice. Dephosphorylation of T522 is critical for repression of its activity during adipogenesis. The phospho‐T522 level is reduced during adipogenesis. Knocking‐in a constitutive T522 phosphorylation mimic activates the β‐catenin/GATA3 pathway, repressing PPARγ signaling, impairing differentiation of white adipocytes, and ameliorating high‐fat diet‐induced dyslipidemia in mice. In contrast, phosphorylation of T522 is crucial for activation of hepatic SIRT1 in response to over‐nutrition. Hepatic SIRT1 is hyperphosphorylated at T522 upon high‐fat diet feeding. Knocking‐in a SIRT1 mutant defective in T522 phosphorylation disrupts hepatic fatty acid oxidation, resulting in hepatic steatosis after high‐fat diet feeding. In addition, the T522 dephosphorylation mimic impairs systemic energy metabolism. Our findings unveil an important link between environmental cues, SIRT1 phosphorylation, and energy homeostasis and demonstrate that the phosphorylation of T522 is a critical element in tissue‐specific regulation of SIRT1 activity in vivo . Synopsis: The phosphorylation of SIRT1 T522 is a critical element in the tissue‐specific regulation of SIRT1 activity in mice. This finding unveils an important link between environmental cues, SIRT1 phosphorylation and energy homeostasis. SIRT1 is dephosphorylated at T522 during normal adipogenesis. Knocking‐in a constitutive T522 phosphorylation mimic activates the β‐catenin/GATA3 pathway, repressing PPARγ signaling and adipogenesis in mice. Hepatic SIRT1 is hyperphosphorylated at T522 upon high‐fat diet feeding. Knocking‐in a SIRT1 mutant defective in T522 phosphorylation disrupts hepatic fatty acid oxidation, resulting in hepatic steatosis in mice on high‐fat diet. Abstract : The phosphorylation of SIRT1 T522 is a critical element in the tissue‐specific regulation of SIRT1 activity in mice. This finding unveils an important link between environmental cues, SIRT1 phosphorylation and energy homeostasis.