Macrophage-induced inflammation is a key contributor to the development of type 2 diabetes and insulin resistance. Palmitate, a saturated fatty acid whose concentration is elevated in patients with type 2 diabetes, can promote macrophage inflammation and is an important factor for the development of type 2 diabetes. Nevertheless, the molecular mechanisms mediating palmitate-induced macrophage activation remain incompletely understood. Here we propose to test a novel hypothesis that changes in protein lysine fatty acylation, which is caused by increased free fatty acids, constitute an important mechanism for obesity-induced type 2 diabetes. We recently showed that palmitate can be internalization and used by cells for lysine (Lys) fatty acylation. We discovered that Lys fatty acylation is an abundant protein modification and identified human SIRT6 as the first robust enzyme to remove fatty acyl groups (such as myristoyl and palmitoyl groups) from protein Lys residues. SIRT6 is a member of class III Lys deacetylases (HDACs), or sirtuin (SIRT1-7), which are known to play an important role in obesity and type 2 diabetes. Our discovery of the efficient defatty-acylation activity of SIRT6 thus challenges a long-standing concept in the HDAC biology that classifies the enzymes as deacetylases. Based on these findings, we hypothesize that Lys fatty acylation and its reversal by SIRT6, at least in part, regulates the metabolic activation of macrophages. In this proposal, we will test this hypothesis by identifying the Lys fatty acylation substrates, in histones and non-histone proteins, and studying their biological functions in both fibroblast and macrophage cells. These studies will reveal key molecule players of Lys fatty acylation pathway in a model system (fibroblast cells) that has been widely used for studying fundamental biology. Our studies will also elucidate the mechanism by which Lys fatty acylation regulates the metabolic activation of macrophages, a cellular system that is physiologically relevant with inflammation, obesity, and diabetes. The knowledge gained from this study will likely have a broad impact on our understanding of histone deacetylases and will lay a foundation for studying Lys fatty acylation, a largely uncharacterized protein modification pathway. The mechanistic understanding of fatty acid-induced metabolic activation of macrophages will help to devise new treatment or preventative strategies for type 2 diabetes and other metabolic diseases.

Public Health Relevance

This project will investigate the role of protein lysine fatty acylation and the protein lysine defatty-acylase SIRT6 in macrophage inflammation, insulin resistance, and type II diabetes. The proposed work will provide important insights into the mechanism of free fatty acids-induced insulin resistance and may provide novel targets for the treatment or prevention of type II diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK107868-02
Application #
9210624
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Sechi, Salvatore
Project Start
2016-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$456,887
Indirect Cost
$83,211
Name
Cornell University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Zhang, Xiaoyu; Spiegelman, Nicole A; Nelson, Ornella D et al. (2017) SIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation. Elife 6:
Kaczmarska, Zuzanna; Ortega, Esther; Goudarzi, Afsaneh et al. (2017) Structure of p300 in complex with acyl-CoA variants. Nat Chem Biol 13:21-29
Sabari, Benjamin R; Zhang, Di; Allis, C David et al. (2017) Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol 18:90-101
Xiong, Xiaozhe; Panchenko, Tatyana; Yang, Shuang et al. (2016) Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat Chem Biol 12:1111-1118
Jiang, Hong; Zhang, Xiaoyu; Lin, Hening (2016) Lysine fatty acylation promotes lysosomal targeting of TNF-?. Sci Rep 6:24371
Aramsangtienchai, Pornpun; Spiegelman, Nicole A; He, Bin et al. (2016) HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine. ACS Chem Biol 11:2685-2692
Zhao, Dan; Guan, Haipeng; Zhao, Shuai et al. (2016) YEATS2 is a selective histone crotonylation reader. Cell Res 26:629-32
Jin, Jing; He, Bin; Zhang, Xiaoyu et al. (2016) SIRT2 Reverses 4-Oxononanoyl Lysine Modification on Histones. J Am Chem Soc 138:12304-7
Li, Yuanyuan; Sabari, Benjamin R; Panchenko, Tatyana et al. (2016) Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain. Mol Cell 62:181-93
Goudarzi, Afsaneh; Zhang, Di; Huang, He et al. (2016) Dynamic Competing Histone H4 K5K8 Acetylation and Butyrylation Are Hallmarks of Highly Active Gene Promoters. Mol Cell 62:169-80

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