Dietary plant stanol esters reduce VLDL cholesterol secretion and bile saturation in apolipoprotein E*3-Leiden transgenic mice

Dietary plant stanols lower serum cholesterol levels in humans and in hyper lipidemic rodents, mainly by inhibition of the intestinal cholesterol absor ption. We used female apolipoprotein E*3-Leiden transgenic mice to investig ate the consequences of this effect on serum lipid levels and hepatic lipid metabolism. Five groups of 6 or 7 mice received for 9 weeks a diet contain ing 0.25% cholesterol and 0.0%, 0.25%, 0.5%, 0.75%, or 1.0% (wt/wt) plant s tanols (sitostanol 88% [wt/wt], campestanol 10% [wt/wt]) esterified to fatt y acids. Compared with the control diet, plant stanol ester treatment dose- dependently reduced serum cholesterol levels by 10% to 33% (P <0.05), mainl y in very low density lipoproteins (VLDLs), intermediate density lipoprotei ns, and low density lipoproteins. Furthermore, 1.0% of the dietary plant st anols significantly decreased the liver contents of cholesteryl esters (-62 %), free cholesterol (-31%), and triglycerides (-38%) but did not change th e hepatic VLDL-triglyceride and VLDL-apolipoprotein B production rates. How ever, plant stanol ester feeding significantly decreased the amounts of cho lesteryl esters and free cholesterol incorporated in nascent VLDLs by 72% a nd 30%, respectively, resulting in a net 2-fold decreased VLDL cholesterol output. Liver mRNA levels of low density lipoprotein receptors, 3-hydroxy-3 -methylglutaryl coenzyme A synthase, cholesterol 7 alpha -hydroxylase, and sterol 27-hydroxylase were not changed by plant stanol ester feeding. Never theless, the serum lathosterol-to-cholesterol ratio was significantly incre ased by 23%, indicating that dietary plant stanol esters increased whole-bo dy cholesterol synthesis. Plant stanol esters also significantly decreased the cholesterol saturation index in bile by 55%. In conclusion, in apolipop rotein E*3-Leiden transgenic mice, plant stanol ester feeding dose-dependen tly lowered serum cholesterol levels as a result of a reduced secretion of VLDL cholesterol. This was caused by a decreased hepatic cholesterol conten t that also resulted in a lowered biliary cholesterol output, indicative of a reduced lithogenicity of bile in these mice.