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



 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.