THE ROLE OF CHOLINE DEPLETION IN PERFLUOROOCTANESULFONATE‐INDUCED HEPATIC STEATOSIS

Abstract

Perfluorooctanesulfonate (PFOS) exposure has resulted in hepatic steatosis and hypolipidemia, believed to be the result of decreased production and secretion of VLDL and HDL and increased uptake of VLDL‐triglyceride. The hypothesis that PFOS produces hepatic steatosis via ionic sequestration of available choline necessary for the production of VLDL was examined. Plausibility was supported by identification of an ion‐triad between two molecules of choline and one molecule of PFOS in vitro. We fed male C57BL/6 mice either a control diet or a marginal methionine/choline‐deficient (mMCD) diet, both with and without PFOS. After a two‐week run‐in period on diets without PFOS, control or mMCD diets containing 0, 30, 60, or 120 mg K+PFOS/kg diet were fed for three weeks. There was a dose‐dependent increase in the relative liver weight in both control and mMCD fed mice. Dietary PFOS was also associated with dose‐dependent decreases in body weight, increases in hepatic triglyceride concentration, and increases in serum ALT, ALP, and bile acids, all with larger effects observed in mice fed mMCD compared to those fed the control diet. Serum and liver concentrations of PFOS were increased in a dose‐dependent manner on both diets; however, serum PFOS concentrations were higher and liver concentrations lower in mMCD‐fed mice compared to corresponding control‐fed mice. Metabolomic analysis demonstrated that PFOS caused a significant decrease in the hepatic concentration of many phosphatidylcholines in the PFOS‐fed mice compared to controls. Further, the average serum concentration of choline was reduced by dietary PFOS. These studies are the first to provide evidence that PFOS may cause hepatic steatosis through depletion of choline required for hepatic VLDL production and export.