Mechanisms for regulation of a novel class of anti-diabetic lipids

一类新型抗糖尿病脂质的调节机制

基本信息

批准号：
10378154
负责人：
BARBARA B. KAHN
金额：
$ 76.03万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378154
关键词：
Adipose tissue Anabolism Anti-Inflammatory Agents Antidiabetic Drugs Antiinflammatory Effect Attention Autoimmune Binding Proteins Biochemical Pathway Biological Assay Biology Biopsy Carbohydrates Clinical Coenzymes Colitis Data Diabetes Mellitus Diglycerides Disease Enzymes Esters Family Family member Fasting Fatty Acids Functional disorder Funding Gene Expression Regulation Genes Genetic Genetic Models Genetic Variation Glucose Health Hepatic High Fat Diet Human Hydrolase Hydrolysis Immune Inbred Strains Mice Incidence Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Isomerism Isotope Labeling Isotopes Knock-out Knockout Mice Knowledge Lead Link Lipase Lipids Lipolysis Liver Measurement Measures Mediating Metabolic Metabolic stress Mild obesity Molecular Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Palmitic Acids Pathogenesis Pathway interactions Persons Phenotype Phospholipase Physiological Physiological Adaptation Plasma Population Positioning Attribute Prevention strategy Proteins Regulation Regulator Genes Regulatory Pathway Resistance Response Elements Risk Role Serum Severities Stable Isotope Labeling Stearic Acids System Systems Analysis Testing Tissues Transacylase Transferase Triglycerides United States National Institutes of Health blood glucose regulation clinically relevant diacylglycerol O-acyltransferase diverse data effective therapy enzyme pathway experimental study fatty acid biosynthesis fatty acid metabolism genetic approach glucose metabolism glucose production glucose tolerance glucose transport human tissue hydroxy fatty acid improved in vivo inhibitor innovation insight insulin secretion insulin sensitivity islet lipid metabolism mouse model novel overexpression prevent protein expression response subcutaneous transcriptome transcriptomics translational potential treatment strategy

项目摘要

The growing epidemic of obesity and Type 2 diabetes requires new strategies for prevention and treatment. We discovered a structurally novel, family of endogenous bioactive lipids, branched fatty Acid esters of Hydroxy fatty Acids (FAHFAs). A subfamily, Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), has anti-diabetic and anti-inflammatory effects. PAHSA levels are low in serum and adipose tissue of insulin-resistant versus insulin-sensitive people, and levels correlate highly with insulin sensitivity. In insulin-resistant mice, PAHSA administration improves glucose tolerance and insulin sensitivity, in part by enhancing insulin action to suppress hepatic glucose production which results from improved lipolysis suppression. PAHSAs are anti-inflammatory and reduce colitis severity and the incidence of auto-immune Type 1 diabetes in mice. We have made tremendous strides in discovering new activities for PAHSAs, identifying additional families of bioactive and storage forms of FAHFAs, and uncovering biochemical pathways and enzymes that control tissue FAHFA levels. These studies underscore that FAHFAs are a highly-regulated class of lipids with tremendous translational potential. The overall objective of this proposal is to determine the mechanisms that regulate tissue and serum FAHFA levels in physiologic and disease states by identifying enzymes and pathways that regulate FAHFA biosynthesis, degradation and incorporation into other lipids. We will use innovative and robust assays we developed with isotopically-labeled FAHFAs and their precursors to measure FAHFA synthesis and degradation in vivo, target specific pathways of FAHFA regulation, and identify additional, missing enzymes and other factors that regulate FAHFA biosynthesis, degradation, transport and storage. We have already made terrific progress by identifying 3 FAHFA hydrolases and the first FAHFA biosynthetic transacylase. We will delineate this new biosynthetic pathway using novel mechanistic studies. We also propose a highly complementary, innovative, systems analyses that will integrate transcriptomic data with targeted FAHFA measurements. First, we will take advantage of the large, reciprocal regulation of FAHFAs in our unique mouse models with altered expression of Glut4 and ChREBP, to find unknown factors mediating this regulation. Since Glut4 and ChREBP expression in adipose tissue from humans correlates with insulin sensitivity and adipose FAHFA levels, genes identified with these experiments could have clinical relevance. The second approach exploits the natural genetic variation in the diversity outbred (DO) mice, which have as much natural genetic variation as the human population. We will perform targeted measurements of ~300 different FAHFA isomers in adipose tissue, liver and plasma of ~500 DO mice and leverage the existing genetic and transcriptomic data from DO mice to find new "drivers"/regulators of tissue FAHFA levels. These studies will advance our understanding of FAHFA biology in health and disease and potentially uncover novel enzymes and pathways in lipid metabolism that can be targeted for clinical benefit.

肥胖和 2 型糖尿病的日益流行需要新的预防和治疗策略。我们发现了一个结构新颖的内源性生物活性脂质家族，即支链脂肪酸酯羟基脂肪酸（FAHFAs）。羟基硬脂酸棕榈酸酯 (PAHSA) 是一个亚家族，具有抗糖尿病和抗炎作用。胰岛素抵抗者血清和脂肪组织中 PAHSA 水平较低与胰岛素敏感人群相比，其水平与胰岛素敏感性高度相关。在胰岛素抵抗的情况下小鼠，PAHSA 给药可部分通过增强胰岛素来改善葡萄糖耐量和胰岛素敏感性抑制肝葡萄糖产生的作用，这是由于改善脂肪分解抑制而产生的。 PAHSA 是抗炎并降低小鼠结肠炎的严重程度和自身免疫性 1 型糖尿病的发病率。我们在发现 PAHSA 的新活性、确定更多的 PAHSA 家族方面取得了巨大进展 FAHFA 的生物活性和储存形式，并揭示控制的生化途径和酶组织FAHFA水平。这些研究强调 FAHFAs 是一类受到高度监管的脂质，巨大的转化潜力。该提案的总体目标是确定以下机制：通过识别酶和在生理和疾病状态下调节组织和血清 FAHFA 水平调节FAHFA生物合成、降解和掺入其他脂质的途径。我们将使用我们利用同位素标记的 FAHFAs 及其前体开发了创新且稳健的检测方法来测量 FAHFA 体内合成和降解，针对 FAHFA 调节的特定途径，并识别额外的、缺失的酶和其他调节FAHFA生物合成、降解、运输和贮存。通过鉴定 3 种 FAHFA 水解酶和第一个 FAHFA，我们已经取得了巨大进展生物合成转酰基酶。我们将利用新颖的机制研究来描述这种新的生物合成途径。我们还提出了一种高度互补、创新的系统分析，将整合转录组数据具有针对性的 FAHFA 测量。首先，我们将利用大规模的互惠监管在我们独特的 Glut4 和 ChREBP 表达改变的小鼠模型中使用 FAHFAs，以发现未知因素调解这一规定。由于人类脂肪组织中的 Glut4 和 ChREBP 表达与胰岛素敏感性和脂肪FAHFA水平，通过这些实验鉴定的基因可能具有临床意义关联。第二种方法利用了多样性远交（DO）小鼠的自然遗传变异，它们具有与人类一样多的自然遗传变异。我们将有针对性地进行对约 500 只 DO 小鼠的脂肪组织、肝脏和血浆中约 300 种不同的 FAHFA 异构体进行了测量利用 DO 小鼠的现有遗传和转录组数据来寻找新的组织“驱动因素”/调节因素 FAHFA 级别。这些研究将增进我们对 FAHFA 生物学在健康和疾病方面的理解潜在地揭示脂质代谢中的新酶和途径，这些酶和途径可用于临床获益。