Effects of organochlorine pesticide exposure on hepatic lipid metabolism in type 2 diabetes

 描述(申请人提供)：在美国，糖尿病的患病率正在以惊人的速度增长。2型糖尿病(T2D)占所有糖尿病诊断病例的90%至95%，其特征是代谢功能障碍，包括糖平衡紊乱，导致高血糖和高胰岛素血症，这是由于胰岛素抵抗的发展。虽然糖平衡紊乱是T2D的标志，但导致肝脏脂肪变性和血脂异常的肝脂代谢异常是一种常见的并存状态。直到最近，还没有假设T2D的环境调解人。然而，最近的流行病学研究以及有限的体内研究表明，接触持久性有机污染物(POPs)的混合物，包括有机氯(OC)杀虫剂DDE、反式壬草胺和环氧氯丹，与胰岛素抵抗、糖尿病、血脂异常和肝脏脂肪变性的患病率显著相关。我们目前的新的初步数据表明，直接暴露于反式九氯或氧氯丹会增加永生化和原代肝细胞内的脂肪积聚，同时伴随着造脂蛋白表达的增加，这表明OC暴露增加了肝脏新生脂肪生成(DNL)，这是诱导肝脏脂肪变性的一种机制。因此，为了进一步进行这些研究，我们将采用体外和体内互补的方法来确定接触有机碳农药扰乱肝脏脂质代谢的生理机制。我们目前的工作假设是，接触OC杀虫剂会促进T2D，其特征是空腹高血糖、胰岛素抵抗和肝功能障碍，包括由于DNL、VLDL分泌和脂肪酸氧化的联合作用而导致的肝脏脂肪变性。这一假说将在以下特定目的进行验证：1.确定有机农药或其代谢产物暴露对基础和胰岛素诱导的肝DNL以及MCA-RH7777肝癌细胞和大鼠原代肝细胞脂肪生成的分子介质的直接影响。2.测定有机氯暴露对肝脏脂质代谢的影响，包括脂肪酸氧化和甘油三酯负荷极低密度脂蛋白的分泌。3.在高脂喂养的2型糖尿病模型中，检测暴露于高流行的有机碳杀虫剂--反式九氢叶酸的能力，以促进T2D，包括导致肝脏脂肪变性和高甘油三酯血症的肝脂代谢紊乱。在本项目成功完成后，将确定暴露于单独的OC杀虫剂扰乱肝脏脂肪代谢的细胞机制，并将确定长期暴露于反式壬草胺对T2D和肝脏脂肪变性的影响。这些信息将扩大我们对T2D发病机制的危险因素的认识，并证实使用OC化合物，特别是反式壬甲草胺作为生物标记物来识别心脏代谢风险增加的患者，并促进早期治疗干预，从而有助于降低T2D及其相关的肝脏脂肪变性和血脂异常的患病率。

 DESCRIPTION (provided by applicant): The prevalence of diabetes mellitus is increasing at a staggering rate in the United States. Type 2 diabetes (T2D) accounts for 90 to 95% of all diagnosed cases of diabetes mellitus and is characterized by metabolic dysfunction including disrupted glucose homeostasis resulting in hyperglycemia and hyperinsulinemia due to the development of insulin resistance. While disrupted glucose homeostasis is the hallmark of T2D, abnormal hepatic lipid metabolism resulting in hepatic steatosis and dyslipidemia is a common co-existing condition. Until recently, an environmental mediator of T2D had not been postulated. However, recent epidemiological studies as well as limited in vivo studies have suggested that exposure to mixtures of persistent organic pollutants (POPs), including the organochlorine (OC) pesticides DDE, trans-nonachlor, and oxychlordane, are significantly correlated with increased prevalence of insulin resistance, diabetes, dyslipidemias, and hepatic steatosis. Our current novel preliminary data indicate direct exposure to trans-nonachlor or oxychlordane increases intracellular lipid accumulation in both immortalized and primary hepatocytes which is accompanied by increased expression of lipogenic proteins suggesting OC exposure increases hepatic de novo lipogenesis (DNL) as a mechanism to induce hepatic steatosis. Therefore, to further these studies, we will determine the physiological mechanisms through which exposure to OC pesticides can disrupt hepatic lipid metabolism using complementary in vitro and in vivo methodologies. Our current working hypothesis is exposure to OC pesticides promotes T2D characterized by increased fasting hyperglycemia, insulin resistance, and hepatic dysfunction including hepatic steatosis resulting from combinatorial actions on DNL, VLDL secretion, and fatty acid oxidation. This hypothesis will be tested in the following specific aims: 1. Determine the direct effect of exposure to OC pesticides or their metabolites on basal and insulin-induced hepatic DNL and molecular mediators of lipogenesis in McA-RH7777 hepatoma cells and rat primary hepatocytes. 2. Determine the effect of organochlorine exposure on hepatic lipid flux including fatty acid oxidation and triglyceride laden VLDL secretion. 3. Examine the ability of exposure to a highly prevalent OC pesticide, trans-nonachlor, to promote T2D including dysfunctional hepatic lipid metabolism resulting in hepatic steatosis and hypertriglyceridemia in a high fat fed model of type 2 diabetes. Upon successful completion of the current project, the cellular mechanisms through which exposure to isolated OC pesticides disrupt hepatic lipid metabolism will be identified and the effect of chronic trans-nonachlor exposure on the development of T2D and hepatic steatosis will be determined. This information will extend our knowledge of contributing risk factors to the pathogenesis of T2D and substantiate the use of OC compounds, especially trans-nonachlor, as biomarkers to identify patients with increased cardiometabolic risk and promote early therapeutic intervention thus aiding in decreasing the prevalence of T2D and associated hepatic steatosis and dyslipidemias.