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EMBO Rep. 2017 May;18(5):841-857. doi: 10.15252/embr.201643803. Epub 2017 Mar 31.

The phosphorylation status of T522 modulates tissue-specific functions of SIRT1 in energy metabolism in mice.

Lu J1,2, Xu Q1, Ji M1, Guo X1, Xu X3, Fargo DC3, Li X4.

Author information

1
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
2
Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
3
Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
4
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA lix3@niehs.nih.gov.

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.

KEYWORDS:

SIRT1; adipogenesis; hepatic steatosis; liver damage; phosphorylation

PMID:
28364022
PMCID:
PMC5412809
DOI:
10.15252/embr.201643803
[Indexed for MEDLINE]
Free PMC Article

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