Effects of ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene
Effects of ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene
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DOI：
10.1053/gast.1996.v111.pm8698195
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发表时间：
1996-07-01
期刊：
影响因子：
29.4
通讯作者：
Offerhaus, GJA
中科院分区：
文献类型：
--
作者：
vanNieuwkerk, CMJ;Elferink, RPJO;Offerhaus, GJA
背景与目的：小鼠 mdr2 基因编码在肝小管膜中表达的 P-糖蛋白。该基因失活会导致胆汁磷脂和胆固醇分泌不足以及非化脓性胆管炎。本研究的目的是探讨胆汁盐疏水性在 mdr2 (-/-) 小鼠肝脏病理诱导中的作用。方法：mdr2 基因 (+/+) 野生型或 (-/-) 敲除小鼠在断奶后 3、6 或 22 周饲喂纯化对照饮食或添加胆酸盐 (0.1%) 或熊去氧胆酸盐 (0.5%) 的饮食。对肝脏组织学进行半定量评分。结果：每只喂食胆汁酸的小鼠成为胆汁盐库的主要成分。 22 周期间的胆酸盐饮食仅在 (+/+) 小鼠中引起非常轻微的肝脏病理变化。相比之下，(-/-) 小鼠的肝脏组织学在 3 周后就已经恶化，并在 75% 的存活小鼠中引起明显的炎症性非化脓性胆管炎和纤维化。与纯化的对照饮食相比，膳食熊去氧胆酸对 (+/+) 小鼠的组织学没有影响，但显着改善 (-/-) 小鼠的肝脏病理学； 22周后，导管增生和门静脉炎症的减少最为明显。结论：mdr2基因敲除小鼠的胆管炎及其后遗症依赖于胆汁盐的疏水性。
Background & Aims: The mouse mdr2 gene encodes a P-glycoprotein expressed in the hepatocanalicular membrane. Inactivation of this gene causes lack of biliary phospholipid and cholesterol secretion and nonsuppurative cholangitis. The aim of this study was to investigate the role of bile salt hydrophobicity in induction of liver pathology in mdr2 (-/-) mice. Methods: Mice (+/+) wild type or (-/-) knockout for the mdr2 gene were fed with either purified control diet or this diet supplemented with cholate (0.1%) or ursodeoxycholate (0.5%) for 3, 6, or 22 weeks after weaning. Liver histology was semiquantitatively scored. Results: Each mouse fed bile acid became the major constituent of the bile salt pool. The cholate diet during 22 weeks induced only very mild liver pathology in (+/+) mice. By contrast, liver histology had already deteriorated after 3 weeks in the (-/-) mice and caused pronounced inflammatory nonsuppurative cholangitis and fibrosis in the 75% of mice that survived. Dietary ursodeoxycholate had no effect on histology in (+/+) mice but improved liver pathology significantly in (-/-) mice compared with purified control diet; the decrease of ductular proliferation and portal inflammation was most prominent after 22 weeks. Conclusions: The cholangiolitis and its sequelae in the mdr2 knockout mice depend on bile salt hydrophobicity.