SIRT6 and lysine fatty acylation in macrophage inflammation

SIRT6 和赖氨酸脂肪酰化在巨噬细胞炎症中的作用

基本信息

批准号：
9009646
负责人：
Hening Lin
金额：
$ 52.43万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9009646
关键词：
Acylation Adipose tissue Affect Binding Biological Models Biological Process Biology Cell Surface Receptors Cells Chemicals Cysteine DNA Data Deacetylation Development Diabetes Mellitus Disease Enzymes Epigenetic Process Event Fatty Acids Fibroblasts Foundations Gene Expression Genes Genetic Transcription Glycine Health Histone Deacetylase Histones Human In Vitro Inflammation Inflammatory Insulin Resistance Knock-out Knowledge Lysine Macrophage Activation Maps Mediating Metabolic Activation Metabolic Diseases Modification Molecular Mus N-terminal Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Palmitates Pathogenesis Pathway interactions Patients Phenotype Physiology Play Post-Translational Protein Processing Prevention Prevention strategy Proteins Proteomics Role Saturated Fatty Acids Signal Transduction Site Solid System TNF gene Testing Transcriptional Regulation Work acyl group amidase base chromatin immunoprecipitation cytokine deep sequencing fatty acylation insight knock-down macrophage member myristoylation non-histone protein novel palmitoylation prevent protein function transcriptome sequencing treatment strategy

项目摘要

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.

描述（由适用提供）：巨噬细胞诱导的感染是导致2型糖尿病和胰岛素抵抗的关键因素。棕榈酸酯是一种饱和脂肪酸，其浓度在2型糖尿病患者中升高，可以促进巨噬细胞感染，并且是2型糖尿病发展的重要因素。然而，介导棕榈酸酯诱导的巨噬细胞激活的分子机制尚不完全了解。在这里，我们提出了一个新的假设，即蛋白质赖氨酸脂肪丙烯酸化的变化是由自由脂肪酸增加引起的，这构成了肥胖引起的2型糖尿病的重要机制。我们最近表明，棕榈酸酯可以是内在的，并被细胞用于赖氨酸（LYS）脂肪丙烯酸化。我们发现Lys脂肪丙烯酸是一种丰富的蛋白质修饰，并将人类SIRT6鉴定为第一个从蛋白质Lys保留中去除脂肪酰基基团（例如Myristoyl和棕榈酰基）的坚固酶。 SIRT6是III类Lys脱乙酰基酶（HDACS）或SIRTUIN（SIRT1-7）的成员，这些成员在肥胖症和2型糖尿病中起着重要作用。因此，我们发现SIRT6的有效缺乏酰化活性的发现，在HDAC生物学中挑战了将酶归类为脱乙酰基酶的长期概念。根据这些发现，我们假设Lys脂肪酰化及其逆转SIRT6至少部分地调节了巨噬细胞的代谢激活。在此提案中，我们将通过识别LYS脂肪酰化来检验该假设在组蛋白和非源蛋白中的底物，并研究其在成纤维细胞和巨噬细胞中的生物学功能。这些研究将揭示在模型系统（成纤维细胞）中广泛用于研究基本生物学的模型系统（成纤维细胞）中的Lys Fatty酰化途径的关键分子参与者。我们的研究还将阐明LYS脂肪酰化调节巨噬细胞代谢激活的机制，巨噬细胞是一种与感染，持有和糖尿病在物理上相关的细胞系统。从这项研究中获得的知识可能会对我们对组蛋白脱乙酰基酶的理解产生广泛的影响，并将为研究Lys Fatty酰基化奠定基础，这是一种很大程度上未表征的蛋白质修饰途径。脂肪酸诱导的巨噬细胞代谢激活的机械理解将有助于制定新的治疗方法或预防2型糖尿病和其他代谢疾病的预防策略。