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

日益流行的肥胖症和2型糖尿病需要新的预防和治疗策略。 我们发现了一种结构新颖的内源生物活性脂类家族，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 具有抗糖尿病和消炎的作用。胰岛素抵抗患者血清和脂肪组织中PAHSA水平较低 与对胰岛素敏感的人相比，水平与胰岛素敏感性高度相关。在胰岛素抵抗方面 小鼠服用PAHSA改善糖耐量和胰岛素敏感性，部分是通过增加胰岛素 抑制肝脏葡萄糖生成的作用，这是由于改善了对脂肪分解的抑制。PAHSA是 抗炎，降低小鼠结肠炎的严重程度和自身免疫性1型糖尿病的发生率。我们 在发现PAHSA的新活动方面取得了巨大进展，识别了更多的 FAHFAs的生物活性和储存形式，以及揭示控制FAHFAs的生化途径和酶 组织中FAHFA水平。这些研究强调，FAHFA是一类高度受监管的脂类，具有 巨大的翻译潜力。这项提案的总体目标是确定 在生理和疾病状态下通过识别酶和血清FAHFA水平调节组织和血清FAHFA 调节FAHFA生物合成、降解和并入其他脂类的途径。我们将使用 我们用同位素标记的FAHFA及其前体开发了创新和强大的分析方法来测量 FAHFA在体内的合成和降解，靶向调控FAHFA的特定途径，并鉴定 另外，缺少酶和其他因素，调节FAHFA的生物合成、降解、运输和 储藏室。我们已经取得了巨大的进展，鉴定了3个FAHFA水解酶和第一个FAHFA 生物合成转酰基酶。我们将使用新的机制研究来描绘这一新的生物合成途径。 我们还提出了一种高度互补性、创新性的系统分析，它将整合转录数据 有针对性的FAHFA测量。首先，我们将利用大的、互惠的监管 我们独特的GLUT4和ChREBP表达改变的小鼠模型中的FAHFAs，以寻找未知因素 调解这一规定。由于人类脂肪组织中GLUT4和ChREBP的表达与 胰岛素敏感性和脂肪FAHFA水平，这些实验确定的基因可能具有临床意义 关联性。第二种方法利用了多样性杂交(DO)小鼠的自然遗传变异， 它们有和人类一样多的自然遗传变异。我们将有针对性地执行 小鼠脂肪组织、肝脏和血浆中~300种FAHFA异构体的测定 利用DO小鼠现有的基因和转录数据来寻找组织的新“驱动力”/调节器 FAHFA水平。这些研究将促进我们对FAHFA生物学在健康和疾病方面的理解 潜在地发现脂代谢中的新的酶和途径，可以作为临床的目标。

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.