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

 描述（由申请人提供）：肥胖、胰岛素抵抗和2型糖尿病的日益流行需要新的预防和治疗策略。我们最近发现了一种结构新颖的生物活性脂质家族，羟基脂肪酸的支链脂肪酸酯（FAHFA），其在体内合成。其中的一个亚类，羟基硬脂酸的棕榈酸酯（PAHSAs），具有抗糖尿病和抗炎作用。在胰岛素抵抗人群中，与胰岛素敏感人群相比，血清和脂肪组织中的PAHSA水平降低，并且水平与胰岛素敏感性高度相关。在胰岛素抵抗小鼠中，PAHSA给药降低血糖，刺激GLP-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，PAHSAs增加胰岛素刺激的葡萄糖转运脂肪细胞和葡萄糖刺激的胰岛素分泌从人胰岛。有8种PAHSA异构体，其酯键的位置不同。PAHSA浓度在生理（禁食）和病理生理（高脂饮食）条件下在许多组织中受到调节。这些新脂质的发现表明它们的合成和降解存在未知的生化途径。本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、降解和分泌在生理和病理生理状态下控制PAHSA水平的相对重要性。我们已经取得了巨大的进展，鉴定了第一个PAHSA水解酶;开发了一个强大的协议，使生物化学纯化的PAHSA生物合成酶的细胞和组织;和体内方法来测量PAHSA的生物合成，降解和分泌清醒的小鼠。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。在这个应用中，我们将整合生物化学，基因组学，分析化学和生理实验，以确定，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。由于PAHSAs有益的生物学效应，这些研究有可能揭示预防和治疗2型糖尿病的新靶点。

 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.