Increased fecal bile acid excretion in transgenic mice with elevated expression of human phospholipid transfer protein

Objective - HDL plays a key role in protection against development of atherosclerosis by promoting reverse cholesterol transport from peripheral tissues to the liver for secretion into bile. Phospholipid transfer protein (PLTP) promotes the transfer of phospholipids between lipoproteins and modulates HDL size and composition, thereby having a crucial role in HDL metabolism. We investigated the effect of increased PLTP activity on removal of cholesterol from the body. Methods and Results - On a chow diet, transgenic mice overexpressing human PLTP have a 15-fold increased plasma PLTP activity compared with wild-type mice (572.4 +/- 59.2 versus 38.6 +/- 3.6 mumol/mL per h). Plasma cholesterol, mainly present in HDL, is strongly decreased (-92%), caused by a rapid clearance from the circulation by the liver and leading to a 1.8-fold increase in hepatic cholesteryl esters. This results in a 2-fold increase in biliary bile acid secretion without changing the bile saturation index. Consequently, the transgenic mice show a 1.4-fold increase in the amount of excreted fecal bile acids compared with wild-type mice, whereas fecal neutral sterol excretion is unchanged. Conclusions - Our data show that elevation of PLTP activity results in rapid disposal of cholesterol from the body via increased conversion into bile acids and subsequent excretion.