Geuken Erwin, Visser Dorien S, Leuvenink Henri G D, de Jong Koert P, Peeters Paul M J G, Slooff Maarten J H, Kuipers Folkert, Porte Robert J
Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, The Netherlands.
Hepatology. 2005 Nov;42(5):1166-74. doi: 10.1002/hep.20886.
The adenosine triphosphate (ATP)-binding cassette (ABC)-transporters ABCG5 and ABCG8 have been shown to mediate hepatic and intestinal excretion of cholesterol. In various (genetically modified) murine models, a strong relationship was found between hepatic expression of ABCG5/ABCG8 and biliary cholesterol content. Our study aimed to relate levels of hepatic expression of ABCG5 and ABCG8 to biliary excretion of cholesterol in man. From 24 patients who had received a liver transplant, bile samples were collected daily after transplantation over a 2-week period to determine biliary composition. Expression of ABCG5, ABCG8, MDR3, and BSEP was assessed by real-time polymerase chain reaction (PCR) in liver biopsy specimens collected before and after transplantation. Levels of hepatic ABCG5, ABCG8, and MDR3 messenger RNA (mRNA) were strongly correlated. After transplantation, the biliary secretion rate of cholesterol continuously increased, coinciding with gradual increases in bile salt and phospholipid secretion. In contrast, hepatic levels of ABCG5 and ABCG8 mRNA remained unchanged. Surprisingly, no correlation was found between the hepatic expression of ABCG5 and ABCG8 and rates of biliary cholesterol secretion, normalized for biliary phospholipid secretion. As expected, the concentration of biliary phospholipids correlated well with MDR3 expression. In conclusion, the strong relationship between ABCG5 and ABCG8 gene expression is consistent with the coordinate regulation of both genes, and in line with heterodimerization of both proteins into a functional transporter. Hepatic ABCG5/ABCG8 expression, at least during the early phase after transplantation, is not directly related to biliary cholesterol secretion in humans. This finding suggests the existence of alternative pathways for the hepatobiliary transport of cholesterol that are not controlled by ABCG5/ABCG8.
三磷酸腺苷（ATP）结合盒（ABC）转运蛋白ABCG5和ABCG8已被证明可介导肝脏和肠道的胆固醇排泄。在各种（基因改造的）小鼠模型中，发现ABCG5/ABCG8的肝脏表达与胆汁胆固醇含量之间存在密切关系。我们的研究旨在探讨ABCG5和ABCG8的肝脏表达水平与人类胆汁胆固醇排泄之间的关系。从24例接受肝移植的患者中，在移植后的2周内每天收集胆汁样本以确定胆汁成分。通过实时聚合酶链反应（PCR）评估移植前后采集的肝活检标本中ABCG5、ABCG8、多药耐药蛋白3（MDR3）和胆汁盐输出泵（BSEP）的表达。肝脏ABCG5、ABCG8和MDR3信使核糖核酸（mRNA）水平密切相关。移植后，胆固醇的胆汁分泌率持续增加，同时胆汁盐和磷脂分泌逐渐增加。相比之下，ABCG5和ABCG8 mRNA的肝脏水平保持不变。令人惊讶的是，在以胆汁磷脂分泌进行标准化后，未发现ABCG5和ABCG8的肝脏表达与胆汁胆固醇分泌率之间存在相关性。正如预期的那样，胆汁磷脂浓度与MDR3表达密切相关。总之，ABCG5和ABCG8基因表达之间的密切关系与这两个基因的协同调节一致，并且与这两种蛋白质异源二聚化形成功能性转运体相符。至少在移植后的早期阶段，肝脏ABCG5/ABCG8表达与人类胆汁胆固醇分泌无直接关系。这一发现表明存在不受ABCG5/ABCG8控制的胆固醇肝胆转运的替代途径。
