TY - JOUR
T1 - Obesity-linked phosphorylation of SIRT1 by casein kinase 2 inhibits its nuclear localization and promotes fatty liver
AU - Choi, Sung E.
AU - Kwon, Sanghoon
AU - Seok, Sunmi
AU - Xiao, Zhen
AU - Lee, Kwan Woo
AU - Kang, Yup
AU - Li, Xiaoling
AU - Shinoda, Kosaku
AU - Kajimura, Shingo
AU - Kemper, Byron
AU - Kemper, Jongsook Kim
N1 - Publisher Copyright:
© 2017 American Society for Microbiology.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Sirtuin1 (SIRT1) deacetylase delays and improves many obesity-related diseases, including nonalcoholic 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. Adenovirus-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. Thus, inhibition of phosphorylation of SIRT1 by CK2 may serve as a new therapeutic approach for treatment of NAFLD and other obesity-related diseases.
AB - Sirtuin1 (SIRT1) deacetylase delays and improves many obesity-related diseases, including nonalcoholic 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. Adenovirus-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. Thus, inhibition of phosphorylation of SIRT1 by CK2 may serve as a new therapeutic approach for treatment of NAFLD and other obesity-related diseases.
KW - Deacetylase
KW - Diabetes
KW - Fatty acid oxidation
KW - NAFLD
KW - PGC-1alpha
KW - Sirtuin
KW - Steatosis
UR - http://www.scopus.com/inward/record.url?scp=85023621567&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85023621567&partnerID=8YFLogxK
U2 - 10.1128/MCB.00006-17
DO - 10.1128/MCB.00006-17
M3 - Article
C2 - 28533219
AN - SCOPUS:85023621567
SN - 0270-7306
VL - 37
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 15
M1 - e00006-17
ER -