Voshol P J, Havinga R, Wolters H, Ottenhoff R, Princen H M, Oude Elferink R P, Groen A K, Kuipers F
Groningen Institute for Drug Studies, Laboratory of Nutrition and Metabolism, University Hospital Groningen, Groningen, The Netherlands.
Gastroenterology. 1998 May;114(5):1024-34. doi: 10.1016/s0016-5085(98)70323-3.
BACKGROUND & AIMS: mdr2 P-glycoprotein (Pgp) deficiency in mice leads to the absence of biliary phospholipids and cholesterol in the presence of normal bile salt secretion. The aim of this study was to evaluate the importance of the biliary pathway in cholesterol homeostasis by determining the effects of mdr2 Pgp deficiency on hepatic and plasma lipid levels and cholesterol kinetics in chow-fed mice.
Hepatic lipid content, enzyme activities, plasma lipoprotein levels, and fecal sterol excretion were measured in wild-type (+/+) and mdr2 Pgp-deficient (-/-) mice. Cholesterol kinetics were determined using radiotracer techniques.
No differences in hepatic lipid content were observed between (-/-) and (+/+) mice. Plasma high-density lipoprotein cholesterol and apolipoprotein A-I levels were strongly reduced in (-/-) mice compared with controls, whereas the apolipoprotein B contents of very-low-density lipoprotein and low-density lipoprotein were increased. Hepatic activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase was threefold greater in (-/-) mice than in controls; however, compartmental analysis of plasma cholesterol decay showed no differences in cholesterol synthesis between (-/-) and (+/+) mice. A dual isotope approach for estimating cholesterol absorption yielded approximately 50% lower values in (-/-) mice than in controls. Surprisingly, (-/-) mice showed a fourfold increase in fecal neutral sterol secretion.
This study unequivocally establishes the important direct role of biliary lipids in the regulation of plasma lipid levels in mice.
小鼠mdr2 P-糖蛋白（Pgp）缺乏导致胆汁盐分泌正常的情况下胆汁中磷脂和胆固醇缺失。本研究旨在通过测定mdr2 Pgp缺乏对正常饮食喂养小鼠肝脏和血浆脂质水平以及胆固醇动力学的影响，评估胆汁途径在胆固醇稳态中的重要性。
测定野生型（+/+）和mdr2 Pgp缺乏型（-/-）小鼠的肝脏脂质含量、酶活性、血浆脂蛋白水平和粪便固醇排泄。使用放射性示踪技术测定胆固醇动力学。
（-/-）和（+/+）小鼠之间未观察到肝脏脂质含量的差异。与对照组相比，（-/-）小鼠的血浆高密度脂蛋白胆固醇和载脂蛋白A-I水平显著降低，而极低密度脂蛋白和低密度脂蛋白的载脂蛋白B含量增加。（-/-）小鼠肝脏3-羟基-3-甲基戊二酰辅酶A还原酶活性比对照组高两倍；然而，血浆胆固醇衰变的区室分析显示（-/-）和（+/+）小鼠之间胆固醇合成无差异。用于估计胆固醇吸收的双同位素方法显示（-/-）小鼠的值比对照组低约50%。令人惊讶的是，（-/-）小鼠的粪便中性固醇分泌增加了四倍。
本研究明确确立了胆汁脂质在调节小鼠血浆脂质水平中的重要直接作用。
