Elferink R P, Ottenhoff R, van Marle J, Frijters C M, Smith A J, Groen A K
Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.
J Clin Invest. 1998 Nov 1;102(9):1749-57. doi: 10.1172/JCI3597.
Cholestasis is associated with hypercholesterolemia and appearance of the abnormal lipoprotein X (LpX) in plasma. Using mice with a disrupted Mdr2 gene, we tested the hypothesis that LpX originates as a biliary lipid vesicle. Mdr2-deficient mice lack Mdr2 P-glycoprotein, the canalicular translocator for phosphatidylcholine, and secrete virtually no phospholipid and cholesterol in bile. Bile duct ligation of Mdr2(+)/+ mice induced a dramatic increase in the plasma cholesterol and phospholipid concentration. Agarose electrophoresis, density gradient ultracentrifugation, gel permeation, and electron microscopy revealed that the majority of phospholipid and cholesterol was present as LpX, a 40-100 nm vesicle with an aqueous lumen. In contrast, the plasma cholesterol and phospholipid concentration in Mdr2(-)/- mice decreased upon bile duct ligation, and plasma fractionation revealed a complete absence of LpX. In mice with various expression levels of Mdr2 or MDR3, the human homolog of Mdr2, we observed that the plasma level of cholesterol and phospholipid during cholestasis correlated very closely with the expression level of these canalicular P-glycoproteins. These data demonstrate that during cholestasis there is a quantitative shift of lipid secretion from bile to the plasma compartment in the form of LpX. The concentration of this lipoprotein is determined by the activity of the canalicular phospholipid translocator.
胆汁淤积与高胆固醇血症以及血浆中异常脂蛋白X（LpX）的出现有关。我们利用Mdr2基因敲除小鼠，检验了LpX起源于胆小管脂质囊泡的假说。Mdr2基因缺陷小鼠缺乏Mdr2 P-糖蛋白，即磷脂酰胆碱的胆小管转运体，几乎不在胆汁中分泌磷脂和胆固醇。对Mdr2(+)/+小鼠进行胆管结扎可导致血浆胆固醇和磷脂浓度显著升高。琼脂糖电泳、密度梯度超速离心、凝胶渗透和电子显微镜检查显示，大部分磷脂和胆固醇以LpX的形式存在，LpX是一种内腔含水的40 - 100 nm囊泡。相反，胆管结扎后Mdr2(-)/-小鼠的血浆胆固醇和磷脂浓度降低，血浆分级分离显示完全不存在LpX。在具有不同Mdr2或其人类同源物MDR3表达水平的小鼠中，我们观察到胆汁淤积期间血浆胆固醇和磷脂水平与这些胆小管P-糖蛋白的表达水平密切相关。这些数据表明，在胆汁淤积期间，脂质分泌以LpX的形式从胆汁向血浆部分发生了定量转移。这种脂蛋白的浓度由胆小管磷脂转运体的活性决定。
