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.

肥胖症和2型糖尿病的流行病已经不断增长，需要采取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，分支的脂肪酸酯羟基脂肪酸（Fahfas）。羟基甲酸（PAHSA）的亚科棕榈酸酯具有抗糖尿病和抗炎作用。 PAHSA水平低胰岛素的血清和脂肪组织与胰岛素敏感的人相比，水平与胰岛素敏感性高度相关。抗胰岛素小鼠，PAHSA给药可提高葡萄糖耐量和胰岛素敏感性，部分通过增强胰岛素抑制肝葡萄糖产生的作用，这是由于改善脂解抑制而产生的。 Pahsas是抗炎和降低结肠炎的严重程度以及小鼠自身免疫1型糖尿病的发生率。我们在发现Pahsas的新活动方面取得了长足的进步，确定了其他家庭 Fahfas的生物活性和存储形式，以及控制控制的生化途径和酶组织法法水平。这些研究强调了法法斯是一类高度调节的脂质，巨大的翻译潜力。该提案的总体目的是确定通过鉴定酶和调节Fahfa生物合成，降解并掺入其他脂质的途径。我们将使用我们使用同位素标记的法法斯及其前体进行了创新和健壮的测定 Fahfa的合成和体内降解，靶向Fahfa调节的特定途径，并识别调节Fahfa生物合成，降解，运输和其他因素的其他因素和其他因素贮存。我们已经通过识别3个Fahfa水解酶和第一个Fahfa取得了惊人的进步生物合成透明酶。我们将使用新型的机械研究来描述这一新的生物合成途径。我们还提出了一个高度互补的，创新的系统分析，以整合转录组数据具有针对性的FAHFA测量。首先，我们将利用大型的相互规定 Fahfas在我们独特的鼠标模型中，glut4和chrebp的表达改变，以找到未知因素调解这一法规。由于来自人类的脂肪组织中的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关联。第二种方法利用了多样性杂种（DO）小鼠的自然遗传变异，与人类人口一样多的自然遗传变异。我们将执行目标在脂肪组织，肝脏和血浆中的〜300种不同FAHFA异构体的测量〜500只小鼠和利用DO小鼠的现有遗传和转录组数据来找到新的“驱动因素”/组织的调节剂法夫水平。这些研究将促进我们对健康和疾病中Fahfa生物学的理解以及有可能发现脂质代谢中的新型酶和途径，可以针对临床益处。