“Trans-nonachlor increases extracellular free fatty acid accumulation and de novo lipogenesis to produce hepatic steatosis in McArdle-RH7777 cells”

Abstract

Recent studies suggest there may be an environmental exposure component to the development and progression of non-alcoholic fatty liver disease (NAFLD) involving the organochlorine (OC) pesticides or their metabolites. However, the roles of OC compounds in the development of NAFLD has not been fully elucidated. Therefore, the current study was designed to determine if exposure to trans-nonachlor, a prevalent OC compound, could promote hepatocyte lipid accumulation and determine potential pro-steatotic mechanisms. McArdle-RH7777 (McA) hepatoma cells were incubated with trans-nonachlor for 24 h then neutral lipid accumulation was determined by Oil Red O staining. Exposure to trans-nonachlor produced a concentration dependent increase in neutral lipid accumulation. Trans-nonachlor also increased extracellular free fatty acid-induced neutral lipid accumulation which appears to be due at least in part to increased free fatty acid accumulation as evident by increased accumulation of Bodipy labeled dodecanoic acid. Additionally, C-acetate incorporation into total cellular lipids was increased by trans-nonachlor implicating increased de novo lipogenesis (DNL) as a potential mediator of trans-nonachlor-induced neutral lipid accumulation. Taken together, the present data indicate exposure to trans-nonachlor has a direct, pro-steatotic effect on hepatocytes to increase lipid accumulation through the combinatorial actions of extracellular free fatty acid accumulation and increased DNL.

Association between Organochlorine Pesticides and Nonalcoholic Fatty Liver Disease in the National Health and Nutrition Examination Survey 2003–2004

“…Previous studies showed that p,p'-DDE was associated with increases in BMI, triglycerides, insulin resistance, and reductions in HDL cholesterol 7,26 . On the other hand, trans-nonachlor has a pro-steatotic effect on hepatocytes in animal experiments 27 . Unlike oxychlordane, NAFLD did not show a signi cant concentration-dependent association with trans-nonachlor in this study, and further studies are needed to clarify this.…”

Association between organochlorine pesticides and nonalcoholic fatty liver disease in the National Health and Nutrition Examination Survey 2003–2004

“…Previous studies showed that p,p′ -DDE was associated with increases in BMI, triglycerides, insulin resistance, and reductions in HDL cholesterol 7 , 23 . In addition, trans-nonachlor has a pro-steatotic effect on hepatocytes in animal experiments 24 . Our study suggests that the prevalence of NAFLD may have an independent association with the concentration of OCPs in the general population, some of which showed a linear dose-dependent relationship.…”

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

“…These data are similar to previously published in vitro data indicating exposure to trans-nonachlor has a direct effect on primary rat hepatocytes or rat hepatoma cells to increase either basal or insulin-stimulated de novo lipogenesis with a corresponding increase in insulinstimulated Fasn production in a cell type specific manner. 19,20 While the current animals were fed .5 or 5 ppm of transnonachlor in LFD or HFD for 16 weeks, it is difficult to equate intake with body burden given the bioaccumulative nature of this compound. 18 Therefore, serum levels of trans-nonachlor were determined at the end of the current study to determine body burden and evaluate how the current exposure levels correspond to known human exposure levels (Figure 7).…”

“…These data are similar to previously published in vitro data indicating exposure to trans-nonachlor has a direct effect on primary rat hepatocytes or rat hepatoma cells to increase either basal or insulin-stimulated de novo lipogenesis with a corresponding increase in insulin-stimulated Fasn production in a cell type specific manner. 19,20…”

“…18 Recent in vitro studies in immortalized and primary rat hepatocytes have demonstrated that exposure to trans-nonachlor can promote hepatocyte lipid accumulation which may be mediated in part by increased de novo lipogenesis. 19,20 These hepatic effects of trans-nonachlor are significant given the key role of the liver in T2D pathogenesis and that hepatic steatosis is a common pathophysiological alteration in T2D.…”