Abcg5/8 independent biliary cholesterol excretion in Atp8b1-deficient mice
Abcg5/8 independent biliary cholesterol excretion in Atp8b1-deficient mice
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DOI：
10.1053/j.gastro.2008.02.097
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发表时间：
2008-06-01
期刊：
影响因子：
29.4
通讯作者：
Elferink, Ronald P. J. Oude
中科院分区：
文献类型：
--
作者：
Groen, Annemiek;Kunne, Cindy;Elferink, Ronald P. J. Oude
背景和目标：ATP 8B 1是小管膜中的磷脂酰丝氨酸翻转酶; ATP 8B 1突变的患者发生重度慢性（PFIC 1）或周期性（BRIC 1）胆汁淤积性肝病。我们已经观察到Atp 8b 1缺乏导致胆汁胆固醇排泄增强。已经确定胆汁胆固醇排泄依赖于异二聚体Abcg 5/Abcg 8的转运。我们假设胆固醇输出增加是由于从改变的小管膜提取增强，而不是更高的Abcg 5/Abcg 8活性。因此，我们研究了Abcg 5/Abcg 8表达和胆固醇排泄的小鼠缺乏Atp 8b 1，Abcg 8，或两者（GF小鼠）之间的关系。方法：在LXR激动剂喂养的野生型小鼠以及缺乏Atp 8b 1或Abcg 8的小鼠中，或在输注牛磺胆酸盐后的GF小鼠中研究胆汁形成。分析胆汁样品的胆固醇、胆盐、磷脂和胞外酶含量。结果如下：LXR激动剂增加Abcg 5/8表达，并且这伴随着野生型和Atp 8b 1（G308 V/G308 V）小鼠的胆汁胆固醇输出增加。然而，Atp 8b 1（G308 V/G308 V）小鼠保持较高的胆固醇输出。虽然在Abcg 8（-/-）小鼠中胆汁胆固醇输出严重减少，但GF小鼠显示出高胆汁胆固醇输出，这与野生型小鼠相当。Atp 8b 1（G308 v/G308 v）和GF小鼠的胆汁显示磷脂酰丝氨酸和鞘磷脂水平升高，表明膜应激。结论：我们的数据表明，增加胆固醇排泄在Atp 8b 1缺陷小鼠是独立的Abcg 5/8活性。这意味着，Atp 8b 1缺陷导致洗涤剂的阻力和随后的非特异性提取胆固醇从小管膜胆汁盐的减少。
Backgrounds & Aims: ATP8B1 is a phosphatidylserine flippase in the canalicular membrane; patients with mutations in ATP8B1 develop severe chronic (PFIC1) or periodic (BRIC1) cholestatic liver disease. We have observed that Atp8b1 deficiency leads to enhanced biliary cholesterol excretion. It has been established that biliary cholesterol excretion depends on transport by the heterodimer Abcg5/Abcg8. We hypothesized that the increased cholesterol output was due to enhanced extraction from the altered canalicular membrane rather than to higher Abcg5/Abcg8 activity. We therefore studied the relation between Abcg5/Abcg8 expression and biliary cholesterol excretion in mice lacking Atp8b1, Abcg8, or both (GF mice). Metho : Bile formation was studied in LXR agonist-fed wild-type mice as well as mice lacking Atp8b1 or Abcg8, or in GF mice upon infusion of taurocholate. Bile samples were analyzed for cholesterol, bile salt, phospholipids, and ectoenzyme content. Results: LXR agonist increased Abcg5/8 expression, and this was accompanied by increased biliary cholesterol output in both wild-type and Atp8b1(G308V/G308V) mice. However, Atp8b1(G308V/G308V) mice maintained higher cholesterol output. Although in Abcg8(-/-) mice biliary cholesterol output was severely reduced, GF mice displayed high biliary cholesterol output, which was comparable with wild-type mice. Bile of both Atp8b1(G308v/G308v) and GF mice displayed elevated levels of phosphatidylserine and sphingomyelin, indicating membrane stress. Conclusions: Our data demonstrate that the increased biliary cholesterol excretion in Atp8b1-deficient mice is independent of Abcg5/8 activity. This implicates that Atp8b1 deficiency leads to a decrease in the detergent resistance and subsequent nonspecific extraction of cholesterol from the canalicular membrane by bile salts.