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.

• Authors: 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
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 37 Issue 15 (08 01 2017) ISSN: 1098-5549 [Electronic] United States
• PMID: 28533219 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 American Society for Microbiology.

Chemical References

• Fatty Acids
• Casein Kinase II
• Sirtuin 1

Topics

• Active Transport, Cell Nucleus
• Animals
• Casein Kinase II (analysis, metabolism)
• Cell Nucleolus (metabolism, pathology)
• Fatty Acids (metabolism)
• Humans
• Liver (metabolism, pathology)
• Male
• Mice, Inbred C57BL
• Models, Molecular
• Non-alcoholic Fatty Liver Disease (etiology, metabolism, pathology)
• Obesity (complications, metabolism, pathology)
• Oxidation-Reduction
• Phosphorylation
• Sirtuin 1 (analysis, metabolism)