Baghdasaryan Anna, Fickert Peter, Fuchsbichler Andrea, Silbert Dagmar, Gumhold Judith, Hörl Gerd, Langner Cord, Moustafa Tarek, Halilbasic Emina, Claudel Thierry, Trauner Michael
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Laboratory of Experimental and Molecular Hepatology, Medical University, Graz, Austria.
Liver Int. 2008 Aug;28(7):948-58. doi: 10.1111/j.1478-3231.2008.01758.x. Epub 2008 Apr 11.
BACKGROUND/AIMS: Multidrug resistance protein 2 (Abcb4) gene knockout mice (Mdr2(-/-)) lack phosphatidylcholine (PC) excretion into bile and spontaneously develop sclerosing cholangitis, biliary fibrosis and hepatocellular carcinomas. We therefore aimed to test whether formation and hepatic retention of abnormal PC metabolites contribute to the pathogenesis of liver injury in Mdr2(-/-) mice.
Mdr2(-/-) mice were either fed a diet supplemented with soybean lecithin 2.5% w/w [phosphatidylcholine-enriched diet (PCD), to increase hepatic PC content] or a choline-deficient diet (CDD, to reduce hepatic PC content) for 4 weeks; controls received chow with energy and nutrient content equivalent to PCD and CDD. Serum liver tests, liver histology, markers of fibrosis, cholangiocyte activation, cell proliferation and thin-layer chromatography for phospholipid (PL) composition were carried out.
PCD decreased serum alkaline phosphatase and total bilirubin levels compared with controls, while liver histology as well as hepatic hydroxyproline content as markers of liver fibrosis did not differ among groups. Both PCD and CDD decreased hepatocellular proliferation compared with controls. Hepatic, serum and biliary PLs remained unchanged despite dietary manipulations and no potentially toxic PL metabolites were detected.
Mdr2(-/-) mice maintain stable hepatic, serum and biliary PL metabolism in response to dietary PC manipulations. Our findings therefore suggest that liver injury in Mdr2(-/-) mice is not due to formation of toxic PL metabolites.
背景/目的：多药耐药蛋白2（Abcb4）基因敲除小鼠（Mdr2(-/-)）缺乏胆汁中磷脂酰胆碱（PC）的排泄，并自发发展为硬化性胆管炎、胆管纤维化和肝细胞癌。因此，我们旨在测试异常PC代谢产物的形成和肝内潴留是否有助于Mdr2(-/-)小鼠肝损伤的发病机制。
给Mdr2(-/-)小鼠喂食补充2.5% w/w大豆卵磷脂的饮食[富含磷脂酰胆碱的饮食（PCD），以增加肝脏PC含量]或胆碱缺乏饮食（CDD，以降低肝脏PC含量）4周；对照组给予能量和营养成分与PCD和CDD相当的普通饲料。进行血清肝功能检查、肝脏组织学检查、纤维化标志物、胆管细胞活化、细胞增殖检查以及磷脂（PL）组成的薄层色谱分析。
与对照组相比，PCD降低了血清碱性磷酸酶和总胆红素水平，而肝脏组织学以及作为肝纤维化标志物的肝脏羟脯氨酸含量在各组之间没有差异。与对照组相比，PCD和CDD均降低了肝细胞增殖。尽管进行了饮食干预，但肝脏、血清和胆汁中的PLs保持不变，且未检测到潜在有毒的PL代谢产物。
Mdr2(-/-)小鼠在饮食PC干预下维持稳定的肝脏、血清和胆汁PL代谢。因此，我们的研究结果表明，Mdr2(-/-)小鼠的肝损伤不是由于有毒PL代谢产物的形成。
