title: The phosphorylation status of T522 modulates tissue-specific functions of SIRT1 in energy metabolism in mice.
abstract: SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, is an important metabolic regulator. However, the mechanisms by which SIRT1 is regulatedin vivoremain 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 activityin vivo.
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.|Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Guo
authors.affiliation: Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Fargo
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA lix3@niehs.nih.gov.
authors.forename: Xiaoling
authors.identifier: 0000-0001-5920-7784
authors.initials: X
authors.lastname: Li
mesh_terms: D017667:Adipocytes / Q000502:physiology; D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D059305:Diet, High-Fat; D050171:Dyslipidemias / Q000235:genetics / Q000503:physiopathology; D004734:Energy Metabolism; D005234:Fatty Liver / Q000235:genetics / Q000503:physiopathology; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D010766:Phosphorylation; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry*
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D013912:Threonine; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: SIRT1; adipogenesis; hepatic steatosis; liver damage; phosphorylation