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

Sung E. Choi, Sanghoon Kwon, Sunmi Seok, Zhen Xiao, Kwan Woo Lee, Yup Kang, Xiaoling Li, Kosaku Shinoda, Shingo Kajimura, Byron Kemper, Jongsook Kim Kemper

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere00006-17
JournalMolecular and Cellular Biology
Volume37
Issue number15
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

Fingerprint

Casein Kinase II
Fatty Liver
Obesity
Phosphorylation
Obese Mice
Glucose Intolerance
Liver
Adenoviridae
Pharmaceutical Preparations
Proteomics
Serine
Fatty Acids
Diet
Non-alcoholic Fatty Liver Disease
Therapeutics

Keywords

  • Deacetylase
  • Diabetes
  • Fatty acid oxidation
  • NAFLD
  • PGC-1alpha
  • Sirtuin
  • Steatosis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Obesity-linked phosphorylation of SIRT1 by casein kinase 2 inhibits its nuclear localization and promotes fatty liver. / Choi, Sung E.; Kwon, Sanghoon; Seok, Sunmi; Xiao, Zhen; Lee, Kwan Woo; Kang, Yup; Li, Xiaoling; Shinoda, Kosaku; Kajimura, Shingo; Kemper, Byron; Kemper, Jongsook Kim.

In: Molecular and Cellular Biology, Vol. 37, No. 15, e00006-17, 01.08.2017.

Research output: Contribution to journalArticle

Choi, SE, Kwon, S, Seok, S, Xiao, Z, Lee, KW, Kang, Y, Li, X, Shinoda, K, Kajimura, S, Kemper, B & Kemper, JK 2017, 'Obesity-linked phosphorylation of SIRT1 by casein kinase 2 inhibits its nuclear localization and promotes fatty liver', Molecular and Cellular Biology, vol. 37, no. 15, e00006-17. https://doi.org/10.1128/MCB.00006-17
Choi, Sung E. ; Kwon, Sanghoon ; Seok, Sunmi ; Xiao, Zhen ; Lee, Kwan Woo ; Kang, Yup ; Li, Xiaoling ; Shinoda, Kosaku ; Kajimura, Shingo ; Kemper, Byron ; Kemper, Jongsook Kim. / Obesity-linked phosphorylation of SIRT1 by casein kinase 2 inhibits its nuclear localization and promotes fatty liver. In: Molecular and Cellular Biology. 2017 ; Vol. 37, No. 15.
@article{7c02c690510f4e0aaf30fdb3300f3dbb,
title = "Obesity-linked phosphorylation of SIRT1 by casein kinase 2 inhibits its nuclear localization and promotes fatty liver",
abstract = "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.",
keywords = "Deacetylase, Diabetes, Fatty acid oxidation, NAFLD, PGC-1alpha, Sirtuin, Steatosis",
author = "Choi, {Sung E.} and Sanghoon Kwon and Sunmi Seok and Zhen Xiao and Lee, {Kwan Woo} and Yup Kang and Xiaoling Li and Kosaku Shinoda and Shingo Kajimura and Byron Kemper and Kemper, {Jongsook Kim}",
year = "2017",
month = "8",
day = "1",
doi = "10.1128/MCB.00006-17",
language = "English (US)",
volume = "37",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "15",

}

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

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

VL - 37

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 15

M1 - e00006-17

ER -