Tang Weiqing, Ma Yinyan, Jia Lin, Ioannou Yiannis A, Davies Joanna P, Yu Liqing
The 5th Clinical Hospital (Beijing Hospital), Peking University, and Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, Ministry of Health, Beijing, China.
J Lipid Res. 2009 Feb;50(2):293-300. doi: 10.1194/jlr.M800439-JLR200. Epub 2008 Sep 15.
Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (NPC1L1(-/-)mice) exhibit a defect in intestinal absorption of cholesterol and phytosterols. However, wild-type (WT) mice do not efficiently absorb and accumulate phytosterols either. Cell-based studies show that NPC1L1 is a much weaker transporter for phytosterols than cholesterol. In this study, we examined the role of NPC1L1 in phytosterol and cholesterol trafficking in mice lacking ATP-binding cassette (ABC) transporters G5 and G8 (G5/G8(-/-) mice). G5/G8(-/-) mice develop sitosterolemia, a genetic disorder characterized by the accumulation of phytosterols in blood and tissues. We found that mice lacking ABCG5/G8 and NPC1L1 [triple knockout (TKO) mice] did not accumulate phytosterols in plasma and the liver. TKO mice, like G5/G8(-/-) mice, still had a defect in hepatobiliary cholesterol secretion, which was consistent with TKO versus NPC1L1(-/-) mice exhibiting a 52% reduction in fecal cholesterol excretion. Because fractional cholesterol absorption was reduced similarly in NPC1L1(-/-) and TKO mice, by subtracting fecal cholesterol excretion in TKO mice from NPC1L1(-/-) mice, we estimated that a 25g NPC1L1(-/-) mouse may secrete about 4 mumol of cholesterol daily via the G5/G8 pathway. In conclusion, NPC1L1 is essential for phytosterols to enter the body in mice.
缺乏尼曼-匹克C1样1蛋白（NPC1L1）的小鼠（NPC1L1基因敲除小鼠）在肠道对胆固醇和植物甾醇的吸收方面存在缺陷。然而，野生型（WT）小鼠也不能有效地吸收和积累植物甾醇。基于细胞的研究表明，NPC1L1作为植物甾醇转运蛋白的能力比胆固醇弱得多。在本研究中，我们研究了NPC1L1在缺乏ATP结合盒（ABC）转运蛋白G5和G8的小鼠（G5/G8基因敲除小鼠）体内植物甾醇和胆固醇转运中的作用。G5/G8基因敲除小鼠会患谷甾醇血症，这是一种以血液和组织中植物甾醇积累为特征的遗传性疾病。我们发现，缺乏ABCG5/G8和NPC1L1的小鼠（三重基因敲除小鼠）血浆和肝脏中没有积累植物甾醇。三重基因敲除小鼠与G5/G8基因敲除小鼠一样，肝胆胆固醇分泌仍存在缺陷，这与三重基因敲除小鼠与NPC1L1基因敲除小鼠相比粪便胆固醇排泄减少52%是一致的。由于NPC1L1基因敲除小鼠和三重基因敲除小鼠的胆固醇吸收分数同样降低，通过用NPC1L1基因敲除小鼠的粪便胆固醇排泄量减去三重基因敲除小鼠的粪便胆固醇排泄量，我们估计一只25克的NPC1L1基因敲除小鼠每天可能通过G5/G8途径分泌约4微摩尔胆固醇。总之，NPC1L1对小鼠体内植物甾醇进入机体至关重要。
