Gallbladder dysfunction caused by MYPT1 ablation triggers cholestasis-induced hepatic fibrosis in mice.

IF 5.6 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Hepatology Communications Pub Date : 2024-06-27 eCollection Date: 2024-07-01 DOI:10.1097/HC9.0000000000000473
Ye Wang, Zhi-Hui Jiang, Yu-Wei Zhou, Tian-Tian Qiu, Han Wang, Min-Sheng Zhu, Xin Chen, Xue-Na Zhang
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引用次数: 0

Abstract

Background: The incidence of gallbladder diseases is as high as 20%, but whether gallbladder diseases contribute to hepatic disorders remains unknown.

Methods: Here, we established an animal model of gallbladder dysfunction and assessed the role of a diseased gallbladder in cholestasis-induced hepatic fibrosis (CIHF).

Results: Mice with smooth muscle-specific deletion of Mypt1, the gene encoding the main regulatory subunit of myosin light chain phosphatase (myosin phosphatase target subunit 1 [MYPT1]), had apparent dysfunction of gallbladder motility. This dysfunction was evidenced by abnormal contractile responses, namely, inhibited cholecystokinin 8-mediated contraction and nitric oxide-resistant relaxation. As a consequence, the gallbladder displayed impaired bile filling and biliary tract dilation comparable to the alterations in CIHF. Interestingly, the mutant animals also displayed CIHF features, including necrotic loci by the age of 1 month and subsequently exhibited progressive fibrosis and hyperplastic/dilated bile ducts. This pathological progression was similar to the phenotypes of the animal model with bile duct ligation and patients with CIHF. The characteristic biomarker of CIHF, serum alkaline phosphatase activity, was also elevated in the mice. Moreover, we observed that the myosin phosphatase target subunit 1 protein level was able to be regulated by several reagents, including lipopolysaccharide, exemplifying the risk factors for gallbladder dysfunction and hence CIHF.

Conclusions: We propose that gallbladder dysfunction caused by myosin phosphatase target subunit 1 ablation is sufficient to induce CIHF in mice, resulting in impairment of the bile transport system.

MYPT1 消融导致的胆囊功能障碍会诱发小鼠胆汁淤积性肝纤维化。
背景:方法:在此,我们建立了胆囊功能障碍的动物模型,并评估了病变胆囊在胆汁淤积诱导的肝纤维化(CIHF)中的作用:结果:编码肌球蛋白轻链磷酸酶主要调节亚基(肌球蛋白磷酸酶靶亚基1 [MYPT1])的基因Mypt1被平滑肌特异性缺失的小鼠具有明显的胆囊运动功能障碍。这种功能障碍表现为异常的收缩反应,即胆囊收缩素 8 介导的收缩和一氧化氮抗性松弛受到抑制。因此,胆囊显示出胆汁充盈受损和胆道扩张,与 CIHF 的改变相当。有趣的是,突变体动物也显示出 CIHF 的特征,包括 1 个月大的坏死位点,随后表现出进行性纤维化和胆管增生/扩张。这种病理进展与胆管结扎动物模型和 CIHF 患者的表型相似。CIHF 的特征性生物标志物--血清碱性磷酸酶活性也在小鼠中升高。此外,我们还观察到肌球蛋白磷酸酶靶亚基 1 蛋白水平可受脂多糖等多种试剂的调节,这体现了胆囊功能障碍进而导致 CIHF 的风险因素:我们认为,肌球蛋白磷酸酶靶亚基 1 消融引起的胆囊功能障碍足以诱发小鼠的 CIHF,导致胆汁运输系统受损。
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来源期刊
Hepatology Communications
Hepatology Communications GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
8.00
自引率
2.00%
发文量
248
审稿时长
8 weeks
期刊介绍: Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction. ​
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