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.

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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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Sechi, Salvatore
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Cornell University
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Huang, He; Zhang, Di; Wang, Yi et al. (2018) Lysine benzoylation is a histone mark regulated by SIRT2. Nat Commun 9:3374
Huang, He; Tang, Shuang; Ji, Ming et al. (2018) p300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis. Mol Cell 70:984
Huang, He; Luo, Zhouqing; Qi, Shankang et al. (2018) Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway. Cell Res 28:111-125
Huang, He; Tang, Shuang; Ji, Ming et al. (2018) EP300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis. Mol Cell 70:663-678.e6
Jiang, Hong; Zhang, Xiaoyu; Chen, Xiao et al. (2018) Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies. Chem Rev 118:919-988
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
Huang, Jing; Luo, Zhouqing; Ying, Wantao et al. (2017) 2-Hydroxyisobutyrylation on histone H4K8 is regulated by glucose homeostasis in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 114:8782-8787
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
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

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