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

 描述(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。我们最近发现了一个结构新颖、具有生物活性的脂类家族，即体内合成的支链脂肪酸羟基脂肪酸酯(FAHFAs)。其中的一个亚类，羟基硬脂酸的棕榈酸酯(PAHSA)，具有抗糖尿病和抗炎的作用。在胰岛素抵抗的人中，血清和脂肪组织中的PAHSA水平比胰岛素敏感的人低，而且水平与胰岛素敏感性高度相关。在胰岛素抵抗的小鼠中，PAHSA可以降低血糖，刺激GLP-1和胰岛素的分泌，改善葡萄糖耐量，并减少脂肪组织中的促炎细胞因子水平。在体外，PAHSA增强胰岛素刺激的脂肪细胞的葡萄糖转运和葡萄糖刺激的人胰岛的胰岛素分泌。有8种PAHSA异构体因酯键的位置不同而不同。在许多组织中，PAHSA浓度在生理(禁食)和病理生理(高脂饮食)条件下受到调节。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。这项建议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、降解和分泌在控制生理和病理生理状态下PAHSA水平的相对重要性。我们已经在鉴定第一个PAHSA水解酶、开发能够从细胞和组织中生化纯化PAHSA生物合成酶的可靠方案以及在清醒小鼠体内测量PAHSA生物合成、降解和分泌方面取得了巨大进展。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。在这一应用中，我们将结合生物化学、基因组学、分析化学和生理实验来鉴定、验证和鉴定PAHSA调节酶，并确定负责控制内源性PAHSA水平的生化途径。由于PAHSA的有益生物效应，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.