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.
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.
摘要：
背景：胆囊疾病的发病率高达20％，但是胆囊疾病是否会导致肝脏疾病仍然未知。
方法：这里，我们建立了胆囊功能障碍的动物模型,并评估了胆囊病变在胆汁淤积诱导的肝纤维化(CIHF)中的作用.
结果：平滑肌特异性缺失的小鼠，该基因编码肌球蛋白轻链磷酸酶的主要调节亚基（肌球蛋白磷酸酶靶亚基1[MYPT1]），有明显的胆囊运动功能障碍。异常的收缩反应证明了这种功能障碍，即,抑制胆囊收缩素8介导的收缩和一氧化氮抵抗的松弛。因此,胆囊表现出的胆汁充盈和胆道扩张受损，与CIHF的改变相当。有趣的是,突变动物还显示了CIHF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增生/扩张的胆管。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，在小鼠中也升高了。此外，我们观察到肌球蛋白磷酸酶靶亚基1蛋白水平能够被几种试剂调节，包括脂多糖,举例说明胆囊功能障碍和因此CIHF的危险因素。
结论：我们建议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导小鼠的CIHF，导致胆汁转运系统受损。
方法：这里，我们建立了胆囊功能障碍的动物模型,并评估了胆囊病变在胆汁淤积诱导的肝纤维化(CIHF)中的作用.
结果：平滑肌特异性缺失的小鼠，该基因编码肌球蛋白轻链磷酸酶的主要调节亚基（肌球蛋白磷酸酶靶亚基1[MYPT1]），有明显的胆囊运动功能障碍。异常的收缩反应证明了这种功能障碍，即,抑制胆囊收缩素8介导的收缩和一氧化氮抵抗的松弛。因此,胆囊表现出的胆汁充盈和胆道扩张受损，与CIHF的改变相当。有趣的是,突变动物还显示了CIHF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增生/扩张的胆管。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，在小鼠中也升高了。此外，我们观察到肌球蛋白磷酸酶靶亚基1蛋白水平能够被几种试剂调节，包括脂多糖,举例说明胆囊功能障碍和因此CIHF的危险因素。
结论：我们建议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导小鼠的CIHF，导致胆汁转运系统受损。
