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

• 批准号: 9210624
• 负责人: Hening Lin
• 金额: $ 50.77万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 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/9210624
• 关键词: Acylation; Adipose tissue; Affect; Binding; Biochemical; Biological Models; Biological Process; Biology; Cell Surface Receptors; Cells; Chemicals; Cysteine; DNA; Data; Deacetylase; Deacetylation; Development; Diabetes Mellitus; Disease; Enzymes; Epigenetic Process; Event; Fatty Acids; Fibroblasts; Foundations; Gene Expression; Genes; Genetic Transcription; Glycine; Histone Deacetylase; Histones; Human; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Knock-out; Knowledge; Lysine; Macrophage Activation; Maps; Mediating; Metabolic; Metabolic Activation; Metabolic Diseases; Modification; Molecular; Mus; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Palmitates; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Physiology; Play; Post-Translational Protein Processing; Prevention; Prevention strategy; Proteins; Proteomics; Role; SIRT1 gene; Saturated Fatty Acids; Signal Transduction; Sirtuins; 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; non-histone protein; novel; prevent; protein function; public health relevance; transcriptome sequencing; treatment strategy

 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型糖尿病发展的重要因素。然而，介导棕榈酸诱导的巨噬细胞活化的分子机制仍不完全清楚。在这里，我们提出了一个新的假设，即蛋白质赖氨酸脂肪酰化的变化，这是由游离脂肪酸的增加，构成了肥胖诱导的2型糖尿病的重要机制。 我们最近发现，棕榈酸可以内化，并用于赖氨酸（Lys）脂肪酰化的细胞。我们发现Lys脂肪酰化是一种丰富的蛋白质修饰，并将人SIRT 6鉴定为第一种从蛋白质Lys残基中去除脂肪酰基（如肉豆蔻酰基和棕榈酰基）的稳健酶。SIRT 6是III类赖氨酸脱乙酰酶（HDAC）或sirtuin（SIRT 1 -7）的成员，已知其在肥胖和2型糖尿病中起重要作用。因此，我们对SIRT 6的有效脱乙酰基活性的发现挑战了HDAC生物学中将酶分类为脱乙酰基酶的长期概念。基于这些发现，我们假设赖氨酸脂肪酰化及其逆转SIRT 6，至少部分，调节巨噬细胞的代谢活化。 在这个提议中，我们将通过鉴定赖氨酸脂肪酰化来验证这一假设。 在组蛋白和非组蛋白蛋白中，研究它们在成纤维细胞和巨噬细胞中的生物学功能。这些研究将揭示已广泛用于基础生物学研究的模型系统（成纤维细胞）中Lys脂肪酰化途径的关键分子参与者。我们的研究还将阐明赖氨酸脂肪酰化调节巨噬细胞代谢活化的机制，巨噬细胞是一种与炎症、肥胖和糖尿病生理相关的细胞系统。从这项研究中获得的知识可能会对我们对组蛋白脱乙酰酶的理解产生广泛的影响，并为研究赖氨酸脂肪酰化（一种很大程度上未表征的蛋白质修饰途径）奠定基础。对脂肪酸诱导的巨噬细胞代谢活化机制的理解将有助于为2型糖尿病和其他代谢疾病设计新的治疗或预防策略。