Obesity-linked phosphorylation of SIRT1 by CK2 inhibits its nuclear localization 2 and promotes fatty liver

SungE Choi, Sanghoon Kwon, Sunmi Seok1, Zhen Xiao, Kwan-Woo Lee, Yup Kang, Xiaoling Li, Kosaku Shinoda, Shingo Kajimura, Byron Kemper and Jongsook Kim Kemper
Molecular and Cellular Biology
Publication Date: 
Mon, 2017-05-22
Sirtuin1 (SIRT1) deacetylase delays and improves many obesity-related diseases, including non-alcoholic fatty liver disease (NAFLD) and diabetes, and has received great attention as a drug target. SIRT1 function is aberrantly low in obesity, so understanding the underlying mechanisms is important for drug development. Here, we show that obesity-linked phosphorylation of SIRT1 inhibits its function and promotes pathological symptoms of NAFLD. In proteomic analysis, Ser-164 was identified as a major serine phosphorylation site in SIRT1 in obese, but not lean, mice, and this phosphorylation was catalyzed by casein kinase-2 (CK2), the levels of which were dramatically elevated in obesity. Mechanistically, phosphorylation of SIRT1 at Ser-164 substantially inhibited its nuclear localization and modestly affected its deacetylase activity. Adenoviral-mediated liver-specific expression of SIRT1 or a phosphor-defective S164A-SIRT1 mutant promoted fatty acid oxidation and ameliorated liver steatosis and glucose intolerance in diet-induced obese mice, but these beneficial effects were not observed in mice expressing a phosphor-mimic S164D-SIRT1 mutant. Remarkably, phosphorylated S164-SIRT1 and CK2 levels were also highly elevated in liver samples of NAFLD patients and correlated with disease severity. Inhibition of phosphorylation of SIRT1 by CK2 may, thus, serve as a new therapeutic approach for treatment of NAFLD and other obesity-related diseases.
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