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

有机氯农药暴露对2型糖尿病肝脂代谢的影响

• 批准号: 9098998
• 负责人: George E Howell
• 金额: $ 43.5万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098998
• 关键词: Accounting; Acetyl-CoA Carboxylase; American; Animal Model; Biological Markers; Carbohydrates; Chlorinated Hydrocarbons; Chronic; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Dichlorodiphenyl Dichloroethylene; Diet; Dietary intake; Disease; Dyslipidemias; Epidemiologic Studies; Epidemiology; Etiology; Exercise; Experimental Models; Exposure to; Fasting; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fatty-acid synthase; Functional disorder; Genetic Predisposition to Disease; Health; Hepatic; Hepatocyte; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; In Vitro; Individual; Insulin; Insulin Resistance; Intervention; Intracellular Accumulation of Lipids; Knowledge; Label; Lauric Acids; Link; Lipids; Liver diseases; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Methodology; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathogenesis; Patients; Physiological; Plasma; Population; Prevalence; Proteins; Rattus; Research; Risk; Risk Factors; Rodent; Role; Serum; Testing; Therapeutic Intervention; Triglycerides; United States; Very low density lipoprotein; Work; basal insulin; blood glucose regulation; cardiometabolic risk; chlorohydrocarbon insecticide; combinatorial; fatty acid oxidation; feeding; glucose metabolism; hepatoma cell; high risk; improved; in vivo; lipid biosynthesis; lipid metabolism; non-alcoholic fatty liver; novel; organochlorine exposure; organochlorine pesticide; organochlorine pesticide exposure; oxychlordane; persistent organic pollutants; public health relevance; screening; uptake

 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.

 描述（由申请人提供）：在美国，糖尿病的患病率正以惊人的速度增加。2型糖尿病（T2 D）占所有糖尿病诊断病例的90 - 95%，其特征在于代谢功能障碍，包括破坏葡萄糖稳态，导致高血糖症和高胰岛素血症，这是由于胰岛素抵抗的发展。虽然破坏葡萄糖稳态是T2 D的标志，但导致肝脏脂肪变性和血脂异常的肝脏脂质代谢异常是常见的共存病症。直到最近，T2 D的环境介质还没有被假定。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（POP）的混合物，包括有机氯（OC）农药DDE，反式-九氯和氧氯草胺，与胰岛素抵抗，糖尿病，血脂异常和肝脂肪变性的患病率增加显着相关。我们目前的新的初步数据表明，直接暴露于反式九氯或羟氯草胺增加细胞内脂质积累的永生化和原代肝细胞，这是伴随着增加的脂肪生成蛋白的表达，表明OC暴露增加肝从头脂肪生成（DNL）作为一种机制，以诱导肝脂肪变性。因此，进一步这些研究，我们将确定的生理机制，通过暴露于OC农药可以破坏肝脏脂质代谢使用互补的体外和体内方法。我们目前的工作假设是暴露于OC农药促进T2 D，其特征在于空腹高血糖症增加、胰岛素抵抗和肝功能障碍，包括由DNL、VLDL分泌和脂肪酸氧化的组合作用引起的肝脂肪变性。这一假设将在以下具体目标进行测试：1。确定暴露于OC农药或其代谢物对McA-RH 7777肝癌细胞和大鼠原代肝细胞中基础和胰岛素诱导的肝DNL和脂肪生成分子介质的直接影响。2.确定有机氯暴露对肝脏脂质通量的影响，包括脂肪酸氧化和载甘油三酯的VLDL分泌。3.在高脂喂养的2型糖尿病模型中，检查暴露于高度流行的OC农药反式-九甲草胺的能力，以促进T2 D，包括导致肝脂肪变性和高脂血症的肝脂质代谢功能障碍。成功完成本项目后，将确定暴露于分离的OC农药破坏肝脏脂质代谢的细胞机制，并确定长期接触反式九甲草胺对2型糖尿病和肝脏脂肪变性发展的影响。这些信息将扩展我们对T2 D发病机制的风险因素的认识，并证实OC化合物，特别是反式-九甲草胺，作为生物标志物的用途，以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T2 D和相关肝脂肪变性和血脂异常的患病率。

项目成果

Alterations in cellular lipid metabolism produce neutral lipid accumulation following exposure to the organochlorine compound trans-nonachlor in rat primary hepatocytes.

• DOI: 10.1002/tox.22583
• 发表时间: 2018-09
• 期刊: Environmental toxicology
• 影响因子: 4.5
• 作者: Howell GE 3rd;McDevitt E;Henein L;Mulligan C;Young D
• 通讯作者: Young D

Alterations of Systemic and Hepatic Metabolic Function Following Exposure to Trans-nonachlor in Low and High Fat Diet Fed Male Sprague Dawley Rats.

• DOI: 10.1177/10915818231170527
• 发表时间: 2023-09
• 期刊: INTERNATIONAL JOURNAL OF TOXICOLOGY
• 影响因子: 2.2
• 作者: McDevitt, Erin;Henein, Lucie;Crawford, Anna;Kondakala, Sandeep;Young, Darian;Meek, Edward;Howell III, George E. E.
• 通讯作者: Howell III, George E. E.

Effects of chlorpyrifos on non-cholinergic toxicity endpoints in immortalized and primary rat hepatocytes under normal and hepatosteatotic conditions.

• DOI: 10.1016/j.tiv.2022.105329
• 发表时间: 2022-04
• 期刊: Toxicology in vitro : an international journal published in association with BIBRA
• 作者: Kondakala S;Henein L;McDevitt E;Ross MK;Howell GE 3rd
• 通讯作者: Howell GE 3rd