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 hyperlipidemic rodents, mainly by inhibition of the intestinal cholesterol absorption. We used female apolipoprotein E*3-Leiden transgenic mice to investigate 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 containing 0.25% cholesterol and 0.0%, 0.25%, 0.5%, 0.75%, or 1.0% (wt/wt) plant stanols (sitostanol 88% [wt/wt], campestanol 10% [wt/wt]) esterified to fatty acids. Compared with the control diet, plant stanol ester treatment dose-dependently reduced serum cholesterol levels by 10% to 33% (P<0.05), mainly in very low density lipoproteins (VLDLs), intermediate density lipoproteins, and low density lipoproteins. Furthermore, 1.0% of the dietary plant stanols significantly decreased the liver contents of cholesteryl esters (-62%), free cholesterol (-31%), and triglycerides (-38%) but did not change the hepatic VLDL-triglyceride and VLDL-apolipoprotein B production rates. However, plant stanol ester feeding significantly decreased the amounts of cholesteryl esters and free cholesterol incorporated in nascent VLDLs by 72% and 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 7alpha-hydroxylase, and sterol 27-hydroxylase were not changed by plant stanol ester feeding. Nevertheless, the serum lathosterol-to-cholesterol ratio was significantly increased by 23%, indicating that dietary plant stanol esters increased whole-body cholesterol synthesis. Plant stanol esters also significantly decreased the cholesterol saturation index in bile by 55%. In conclusion, in apolipoprotein E*3-Leiden transgenic mice, plant stanol ester feeding dose-dependently lowered serum cholesterol levels as a result of a reduced secretion of VLDL cholesterol. This was caused by a decreased hepatic cholesterol content that also resulted in a lowered biliary cholesterol output, indicative of a reduced lithogenicity of bile in these mice.
Volger
O L
OL
TNO Prevention and Health, Leiden, the Netherlands.
van der Boom
H
H
de Wit
E C
EC
van Duyvenvoorde
W
W
Hornstra
G
G
Plat
J
J
Havekes
L M
LM
Mensink
R P
RP
Princen
H M
HM
D000818:Animals; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics*; D001646:Bile / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood / Q000378:metabolism*; D004032:Diet; D005260:Female; D000960:Hypolipidemic Agents / Q000097:blood / Q000494:pharmacology*; D008074:Lipoproteins / Q000097:blood; D008079:Lipoproteins, VLDL / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012855:Sitosterols / Q000097:blood / Q000494:pharmacology*
D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D015243:Cholesterol, VLDL; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D012855:Sitosterols; C052720:apolipoprotein E3 (Leidein); C407042:plant stanol ester; C001521:lathosterol; D002784:Cholesterol