SIRT6 and lysine fatty acylation in macrophage inflammation

 描述(申请人提供)：巨噬细胞诱导的炎症是2型糖尿病和胰岛素抵抗发展的关键因素。棕榈酸酯是一种饱和脂肪酸，在2型糖尿病患者中浓度升高，可促进巨噬细胞炎症，是2型糖尿病发生的重要因素。然而，棕榈酸酯诱导巨噬细胞活化的分子机制仍不完全清楚。在这里，我们建议检验一个新的假说，即由游离脂肪酸增加引起的蛋白质赖氨酸脂肪酰化的变化构成肥胖诱导的2型糖尿病的一个重要机制。我们最近发现棕榈酸酯可以内化并被细胞用来进行赖氨酸(Lys)的脂肪酰化。我们发现Lys脂肪酰化是一种丰富的蛋白质修饰，并确定人类SIRT6是第一个从蛋白质Lys残基中去除脂肪酰基(如肉豆蔻基和棕榈酰基)的强健酶。SIRT6是III型赖氨酸脱乙酰酶(HDACs)或sirtuin(SIRT1-7)的成员，已知在肥胖症和2型糖尿病中发挥重要作用。因此，我们对SIRT6高效脱脂酰化活性的发现挑战了HDAC生物学中一个长期存在的概念，即将这些酶归类为脱乙酰酶。基于这些发现，我们推测Lys脂肪酰化及其被SIRT6逆转，至少部分地调节巨噬细胞的代谢激活。在这项提议中，我们将通过鉴定赖氨酸脂肪酰化来检验这一假说 组蛋白和非组蛋白中的底物，并研究它们在成纤维细胞和巨噬细胞中的生物学功能。这些研究将在广泛用于基础生物学研究的模型系统(成纤维细胞)中揭示赖氨酸脂肪酰化途径的关键分子。我们的研究还将阐明赖氨酸脂肪酰化调节巨噬细胞代谢激活的机制，巨噬细胞是一个与炎症、肥胖和糖尿病具有生理相关性的细胞系统。这项研究所获得的知识可能会对我们理解组蛋白脱乙酰酶产生广泛的影响，并将为研究赖氨酸脂肪酰化奠定基础，赖氨酸脂肪酰化是一种在很大程度上尚未确定的蛋白质修饰途径。了解脂肪酸诱导巨噬细胞代谢激活的机制将有助于设计新的治疗或预防2型糖尿病和其他代谢性疾病的策略。

 DESCRIPTION (provided by applicant): 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.