Adeno-associated virus-based caveolin-1 delivery via different routes for the prevention of cholesterol gallstone formation.
Adeno-associated virus-based caveolin-1 delivery via different routes for the prevention of cholesterol gallstone formation.
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基于腺相关病毒的caveolin-1通过不同途径递送以预防胆固醇胆结石形成
DOI：
10.1186/s12944-022-01718-7
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发表时间：
2022-10-27
影响因子：
4.5
通讯作者：
Xu, Guoqiang
中科院分区：
文献类型：
--
作者：
Li, Sha;Chen, Hongtan;Jiang, Xin;Hu, Fengling;Li, Yiqiao;Xu, Guoqiang
关键词：
肝小窝蛋白-1（CAV 1）在胆固醇结石病（CGD）中减少。CAV 1缺陷小鼠易发生CGD。然而，它仍然是未知的恢复肝CAV 1表达是否阻止CGD的发展。将携带CAV 1基因的腺相关病毒2/8（AAV 2/8）载体（AAV 2/8 CAV 1）通过静脉内（i. v.）或腹膜内（i. p.）途径，然后进行致石饮食（LD）8周。未注射的小鼠用作对照。检查了通过静脉内或腹膜内AAV 2/8 CAV 1处理来挽救CAV 1表达以预防CGD的功能后果及其随后的分子机制。LD喂养的CGD小鼠的肝脏和胆囊中的CAV 1表达减少。我们发现，AAV 2/8 CAV 1腹膜内递送导致胆囊中比尾静脉施用更高的转导效率。尽管静脉或腹腔注射AAV 2/8 CAV 1改善了CGD小鼠的肝脏脂质代谢异常，但不影响LD喂养诱导的胆汁胆固醇过饱和。与静脉注射给药途径相比，腹腔注射AAV 2/8 CAV 1明显增加了LD喂养小鼠胆囊中CAV 1蛋白水平，并且腹腔注射AAV 2/8 CAV 1部分提高了胆囊胆囊收缩素受体（CCKAR）的反应性，并通过激活腺苷一磷酸活化蛋白激酶（AMPK）信号通路阻止胆汁胆固醇成核，其诱导胆囊粘蛋白-1（MUC 1）和MUC 5ac表达的减少以及胆囊胆固醇积累。通过腹膜内注射AAV 2/8 CAV 1预防LD喂养的小鼠中的CGD与胆囊淤滞的改善相关，这再次支持了过饱和胆汁对于胆固醇胆结石的形成是必需的但不足够的观点。此外，通过局部腹膜内注射的AAV治疗提供了比全身静脉内途径更有效的胆囊基因递送的特别优势，这将是进行关于维持正常胆囊功能以预防CGD的临床前功能研究的极好工具。在线版本包含补充材料，可通过10.1186/s12944-022-01718-7获得。
Hepatic caveolin-1 (CAV1) is reduced in cholesterol gallstone disease (CGD). Mice with CAV1 deficiency were prone to develop CGD. However, it remains unknown whether restored hepatic CAV1 expression prevents the development of CGD. C57BL/6 mice were injected with adeno-associated virus 2/8 (AAV2/8) vectors carrying the CAV1 gene (AAV2/8CAV1) via intravenous (i.v.) or intraperitoneal (i.p.) route and then subjected to a lithogenic diet (LD) for 8 weeks. Uninjected mice were used as controls. The functional consequences of rescuing CAV1 expression by either i.v. or i.p. AAV2/8CAV1 treatment for CGD prevention and its subsequent molecular mechanisms were examined. CAV1 expression was reduced in the liver and gallbladder of LD-fed CGD mice. We discovered that AAV2/8CAV1 i.p. delivery results in higher transduction efficiency in the gallbladder than tail vein administration. Although either i.v. or i.p. injection of AAV2/8CAV1 improved liver lipid metabolic abnormalities in CGD mice but did not affect LD feeding-induced bile cholesterol supersaturation. In comparison with i.v. administration route, i.p. administration of AAV2/8CAV1 obviously increased CAV1 protein levels in the gallbladder of LD-fed mice, and i.p. delivery of AAV2/8CAV1 partially improved gallbladder cholecystokinin receptor (CCKAR) responsiveness and impeded bile cholesterol nucleation via the activation of adenosine monophosphate-activated protein kinase (AMPK) signaling, which induced a reduction in gallbladder mucin-1 (MUC1) and MUC5ac expression and gallbladder cholesterol accumulation. CGD prevention by i.p. AAV2/8CAV1 injection in LD-fed mice was associated with the improvement of gallbladder stasis, which again supported the notion that supersaturated bile is required but not sufficient for the formation of cholesterol gallstones. Additionally, AAV treatment via the local i.p. injection offers particular advantages over the systemic i.v. route for much more effective gallbladder gene delivery, which will be an excellent tool for conducting preclinical functional studies on the maintenance of normal gallbladder function to prevent CGD. The online version contains supplementary material available at 10.1186/s12944-022-01718-7.
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影响因子：
9
作者：
Han, Mei;Pioronska, Weronika;Meyer, Christoph
通讯作者：
Meyer, Christoph
影响因子：
9.2
作者：
Bosch, Marta;Mari, Montserrat;Herms, Albert;Fernandez, Ana;Fajardo, Alba;Kassan, Adam;Giralt, Albert;Colell, Anna;Balgoma, David;Barbero, Elisabet;Gonzalez-Moreno, Elena;Matias, Nuria;Tebar, Francesc;Balsinde, Jesus;Camps, Marta;Enrich, Carlos;Gross, Steven P.;Garcia-Ruiz, Carmen;Perez-Navarro, Esther;Fernandez-Checa, Jose C.;Pol, Albert
通讯作者：
Pol, Albert
影响因子：
20.1
作者：
Kohlstedt, Karin;Trouvain, Caroline;Fleming, Ingrid
通讯作者：
Fleming, Ingrid
影响因子：
4.6
作者：
Ramzy, Adam;Tuduri, Eva;Kieffer, Timothy J.
通讯作者：
Kieffer, Timothy J.
影响因子：
7.5
作者：
Sohn J;Lin H;Fritch MR;Tuan RS
通讯作者：
Tuan RS