Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex
Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex
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DOI：
10.1002/hep.25861
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发表时间：
2012-11-01
期刊：
影响因子：
13.5
通讯作者：
Rudling, Mats
中科院分区：
文献类型：
--
作者：
Bonde, Ylva;Plosch, Torsten;Rudling, Mats
将胆固醇分泌到胆汁中对于从体内消除胆固醇是重要的。甲状腺激素（TH）增加胆汁胆固醇分泌和三磷酸腺苷（ATP）-结合盒，亚家族G（白色），成员5（ABCG 5）和ATP-结合盒，亚家族G（白色），成员8（ABCG 8）的肝脏基因表达，这两种半转运蛋白充当促进固醇分泌的异二聚体复合物。此外，也受TH调节的核肝X受体-α（LXRa）诱导ABCG 5/G8的基因表达。我们在这里调查，如果TH诱导的刺激胆汁胆固醇分泌介导的ABCG 5/G8复合物在体内，如果是这样，是否涉及LXR。用三碘甲状腺原氨酸（T3）处理Abcg 5（Abcg 5（-/-））或Lxra（Lxra（-/-））破坏纯合小鼠及其野生型对应物14天，并与相应遗传背景的未处理小鼠进行比较。通过胆囊插管收集胆汁，并分析肝脏样品的基因表达水平。Abcg 5（-/-）小鼠的基础胆汁胆固醇分泌比Abcg 5（+/+）小鼠低72%。T3处理使Abcg 5（+/+）小鼠的胆固醇分泌增加3.1倍，而这种反应在Abcg 5（-/-）小鼠中严重减弱。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，并且没有显著差异。结论：TH诱导的胆固醇分泌到胆汁中在很大程度上依赖于完整的ABCG 5/G8转运蛋白复合物，而LXR α对这种作用并不重要。（肝脏学2012;56：18281837）
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. (HEPATOLOGY 2012;56:18281837)