Regulation of the biosynthesis of a novel class of anti-diabetic lipids

一类新型抗糖尿病脂质生物合成的调节

基本信息

批准号：
9895741
负责人：
BARBARA B. KAHN
金额：
$ 70.73万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
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：
2016-04-20 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895741
关键词：
Adipocytes Adipose tissue Affect Anabolism Analytical Chemistry Anti-Inflammatory Agents Antidiabetic Drugs Antiinflammatory Effect Attention Biochemical Biochemical Pathway Biochemistry Biological Biology Blood Glucose CRISPR/Cas technology Carboxylesterase 1 Cells Data Development Diabetes Mellitus Disease Enzymes Esters Family Fasting Fatty Acids Genomics Glucose Glucose Intolerance Goals High Fat Diet Homologous Gene Human Human Activities Hydrolase In Situ In Vitro Inflammatory Insulin Insulin Resistance Islets of Langerhans Isomerism Knock-out Knockout Mice Knowledge Label Lead Link Lipids Liver Measures Metabolic Metabolic Diseases Methods Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutritional Obesity Obesity Epidemic Palmitic Acids Pathogenesis Pathway interactions Physiological Positioning Attribute Prevention strategy Process Protocols documentation Regulation Risk Role Serum Specificity Stearic Acids Structure Therapeutic Tissues awake carboxylesterase cytokine effective therapy experimental study glucagon-like peptide 1 glucose metabolism glucose tolerance glucose transport human tissue hydroxy fatty acid improved in vivo inhibitor/antagonist insight insulin secretion insulin sensitivity lipid biosynthesis lipid metabolism metabolic abnormality assessment novel novel strategies overexpression prevent public health relevance treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The growing epidemic of obesity, insulin resistance, and Type 2 diabetes requires new strategies for prevention and treatment. We recently discovered a structurally novel, bioactive family of lipids, branched Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs), which are synthesized in vivo. A subclass of these, Palmitic Acid esters of Hydroxy Stearic Acid (PAHSAs), have anti-diabetic and anti-inflammatory effects. In insulin-resistant people, PAHSA levels in serum and adipose tissue are reduced compared to insulin-sensitive people, and levels correlate highly with insulin sensitivity. In insulin-resistant mice, PAHSA administration lowers blood glucose, stimulates GLP-1 and insulin secretion, improves glucose tolerance and reduces pro-inflammatory cytokine levels in adipose tissue. In vitro, PAHSAs augment insulin-stimulated glucose transport in adipocytes and glucose-stimulated insulin secretion from human pancreatic islets. There are 8 PAHSA isomers that differ by the position of the ester bond. PAHSA concentrations are regulated under physiologic (fasting) and pathophysiologic (high-fat diet) conditions in numerous tissues. The discovery of these novel lipids indicates the existence of unknown biochemical pathways for their synthesis and degradation. The overall goal of this proposal is to identify the enzymes that regulate the biosynthesis and degradation of PAHSAs, and to determine the relative importance of synthesis, degradation and secretion in controlling PAHSA levels in physiologic and pathophysiologic states. We have already made tremendous progress with the identification of the first PAHSA hydrolase; the development of a robust protocol that enables the biochemical purification of PAHSA biosynthetic enzymes from cells and tissues; and in vivo methods to measure PAHSA biosynthesis, degradation and secretion in awake mice. These studies will enable us to determine the relative contributions of these processes to PAHSA regulation and which mechanisms are responsible for lowering PAHSA levels in insulin-resistant states. In this application, we will integrate biochemistry, genomics, analytical chemistry and physiological experiments to identify, validate and characterize PAHSA regulatory enzymes, and to define the biochemical pathways that are responsible for controlling endogenous PAHSA levels. Because of the beneficial biologic effects of PAHSAs, these studies have the potential to reveal new targets to prevent and treat type 2 diabetes.

描述（由申请人提供）：日益流行的肥胖、胰岛素抵抗和 2 型糖尿病需要新的预防和治疗策略。我们最近发现了一种结构新颖、具有生物活性的脂质家族，即羟基脂肪酸的支链脂肪酸酯 (FAHFAs)。），它们是体内合成的一个亚类，羟基硬脂酸棕榈酸酯（PAHSA）具有抗糖尿病和抗糖尿病作用。与胰岛素敏感的人相比，胰岛素抵抗的人血清和脂肪组织中的 PAHSA 水平降低，并且在胰岛素抵抗的小鼠中，PAHSA 的水平与胰岛素敏感性高度相关。 1 和胰岛素分泌，改善葡萄糖耐量并降低脂肪组织中的促炎细胞因子水平。在体外，PAHSA 增强脂肪细胞中胰岛素刺激的葡萄糖转运以及人类胰岛中葡萄糖刺激的胰岛素分泌。 8 种不同酯键位置的 PAHSA 异构体在许多组织的生理（禁食）和病理生理（高脂肪饮食）条件下受到调节。这些新型脂质的发现表明其存在未知的生化途径。该提案的总体目标是确定调节 PAHSA 生物合成和降解的酶，并确定合成、降解和分泌在控制 PAHSA 水平中的相对重要性。我们已经在鉴定第一个 PAHSA 水解酶方面取得了巨大进展；开发了一种能够从细胞和组织中生化纯化 PAHSA 生物合成酶的方法，以及测量 PAHSA 生物合成和降解的体内方法；这些研究将使我们能够确定这些过程对 PAHSA 调节的相对贡献，以及哪些机制负责降低胰岛素抵抗状态下的 PAHSA 水平。在应用中，我们将整合生物化学、基因组学、分析化学和生理学实验来识别、验证和表征 PAHSA 调节酶，并确定负责控制内源性 PAHSA 水平的生化途径，因为 PAHSA 具有有益的生物学作用。有潜力揭示预防和治疗 2 型糖尿病的新目标。