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甲状腺激素刺激鼠胆甾醇分泌依赖于 ABCG5/G8 功能复合物。

Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex.

机构信息

Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.

出版信息

Hepatology. 2012 Nov;56(5):1828-37. doi: 10.1002/hep.25861. Epub 2012 Oct 14.

DOI:10.1002/hep.25861
PMID:22829162
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3533177/
Abstract

UNLABELLED

Secretion of cholesterol into bile is important for the elimination of cholesterol from the body. Thyroid hormone (TH) increases biliary cholesterol secretion and hepatic gene expression of adenosine triphosphate (ATP)-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and ATP-binding cassette, subfamily G (WHITE), member 8 (ABCG8), two half-transporters that act as a heterodimeric complex promoting sterol secretion. In addition, nuclear liver x receptor-alpha (LXRa), also regulated by TH, induces gene expression of ABCG5/G8. We here investigated if the TH-induced stimulation of biliary cholesterol secretion is mediated by the ABCG5/G8 complex in vivo, and if so, whether LXRa is involved. Mice homozygous for disruption of Abcg5 (Abcg5(-/-) ) or Lxra (Lxra(-/-) ) and their wild-type counterparts were treated with triiodothyronine (T3) for 14 days and compared to untreated mice of corresponding genetic backgrounds. Bile was collected by gallbladder cannulation, and liver samples were analyzed for gene expression levels. Basal biliary cholesterol secretion in Abcg5(-/-) mice was 72% lower than in Abcg5(+/+) mice. T3 treatment increased cholesterol secretion 3.1-fold in Abcg5(+/+) mice, whereas this response was severely blunted in Abcg5(-/-) mice. In contrast, biliary cholesterol secretion in T3-treated Lxra(+/+) and Lxra(-/-) mice was increased 3.5- and 2.6-fold, respectively, and did not differ significantly.

CONCLUSIONS

TH-induced secretion of cholesterol into bile is largely dependent on an intact ABCG5/G8 transporter complex, whereas LXRa is not critical for this effect.

摘要

未加标签

胆固醇向胆汁中的分泌对于从体内清除胆固醇很重要。甲状腺激素 (TH) 增加胆汁胆固醇分泌和肝脏三磷酸腺苷 (ATP)-结合盒，G 超家族成员 5 (ABCG5) 和 ATP-结合盒，G 超家族成员 8 (ABCG8) 的基因表达，这两种半转运体作为促进固醇分泌的异二聚体复合物起作用。此外，核受体肝 X 受体-α (LXRa) 也受 TH 调节，诱导 ABCG5/G8 的基因表达。我们在此研究了 TH 诱导的胆汁胆固醇分泌刺激是否在体内通过 ABCG5/G8 复合物介导，如是，LXRa 是否参与其中。Abcg5（Abcg5(-/-)）或 Lxra（Lxra(-/-)）基因敲除的杂合子小鼠及其野生型对照在给予三碘甲状腺原氨酸 (T3) 14 天后进行了治疗，并与相应遗传背景的未治疗小鼠进行了比较。通过胆囊插管收集胆汁，并分析肝样品的基因表达水平。Abcg5(-/-) 小鼠的基础胆汁胆固醇分泌量比 Abcg5(+/+) 小鼠低 72%。T3 处理使 Abcg5(+/+) 小鼠的胆固醇分泌增加 3.1 倍，而 Abcg5(-/-) 小鼠的这种反应则严重减弱。相比之下，T3 处理的 Lxra(+/+) 和 Lxra(-/-) 小鼠的胆汁胆固醇分泌分别增加了 3.5 倍和 2.6 倍，差异无统计学意义。

结论

TH 诱导的胆固醇向胆汁中的分泌在很大程度上依赖于完整的 ABCG5/G8 转运体复合物，而 LXRa 对于该效应并非关键。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09ef/3533177/86fe8a9ed164/hep0056-1828-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09ef/3533177/f441f4038b54/hep0056-1828-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09ef/3533177/3a33ba227d99/hep0056-1828-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09ef/3533177/4d225e6edaa2/hep0056-1828-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09ef/3533177/86fe8a9ed164/hep0056-1828-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09ef/3533177/f441f4038b54/hep0056-1828-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09ef/3533177/3a33ba227d99/hep0056-1828-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09ef/3533177/4d225e6edaa2/hep0056-1828-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09ef/3533177/86fe8a9ed164/hep0056-1828-f4.jpg

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