Metformin slows liver cyst formation and fibrosis in experimental model of polycystic liver disease
Metformin slows liver cyst formation and fibrosis in experimental model of polycystic liver disease
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二甲双胍可减缓多囊肝实验模型中的肝囊肿形成和纤维化
DOI：
10.1152/ajpgi.00120.2020
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发表时间：
2021
影响因子：
4.5
通讯作者：
Ito Osamu
中科院分区：
文献类型：
--
作者：
Sato Yoichi;Qiu Jiahe;Hirose Takuo;Miura Takahiro;Sato Yasunori;Kohzuki Masahiro;Ito Osamu
多囊性肝病（Polycystic liver disease， PLD）是一种遗传性肝病，囊肿数量随着时间的推移而增加，引起各种腹部症状和生活质量差。虽然PLD的有效治疗方法尚未建立，但我们最近报道了长期运动可以通过活化多囊肾（PCK）大鼠（一种PLD模型）的amp活化蛋白激酶（AMPK）改善肝囊肿形成和纤维化。因此，本研究的目的是研究二甲双胍，一种间接AMPK激活剂，是否对PCK大鼠有效。将PCK大鼠随机分为对照组（Con）和二甲双胍治疗组（Met）。Met组在饮水中口服二甲双胍。12周后，检测各组肝脏功能、组织学和PLD信号级联。二甲双胍不影响体重和肝脏重量，但减少肝囊肿形成、胆管细胞增殖和囊肿周围纤维化。二甲双胍增加了AMPK和结节硬化复合体2的磷酸化，降低了哺乳动物雷帕霉素靶蛋白、S6和细胞外信号调节激酶的磷酸化以及囊性纤维化跨膜传导调节剂、水通道蛋白I、转化生长因子-β和1型胶原的表达，而肝脏中凋亡和胶原降解因子未发生变化。二甲双胍通过激活AMPK和抑制PCK大鼠肝脏中负责细胞增殖和纤维化的信号级联，减缓囊肿形成和纤维化的发展。新的和值得注意的是，这项研究表明，二甲双胍，一种间接AMPK激活剂，可以减缓PLD大鼠模型中肝囊肿的形成和纤维化。二甲双胍通过mTOR和ERK通路的失活来减弱肝脏中过度的细胞增殖。二甲双胍还能降低负责囊性液体分泌和肝纤维化的蛋白质的表达。二甲双胍和AMPK激活剂可能是治疗多囊性肝病的有效药物。
Polycystic liver disease (PLD) is a hereditary liver disease in which the number of cysts increases over time, causing various abdominal symptoms and poor quality of life. Although effective treatment for PLD has not been established, we recently reported that long-term exercise ameliorated liver cyst formation and fibrosis with the activation of AMP-activated protein kinase (AMPK) in polycystic kidney (PCK) rats, a PLD model. Therefore, the aim of this study was to investigate whether metformin, an indirect AMPK activator, was effective in PCK rats. PCK rats were randomly divided into a control (Con) group and a metformin-treated (Met) group. The Met group was treated orally with metformin in drinking water. After 12 wk, liver function, histology, and signaling cascades of PLD were examined in the groups. Metformin did not affect the body weight or liver weight, but it reduced liver cyst formation, cholangiocyte proliferation, and fibrosis around the cyst. Metformin increased the phosphorylation of AMPK and tuberous sclerosis complex 2 and decreased the phosphorylation of mammalian target of rapamycin, S6, and extracellular signal-regulated kinase and the expression of cystic fibrosis transmembrane conductance regulator, aquaporin I, transforming growth factor-β, and type 1 collagen without changes in apoptosis or collagen degradation factors in the liver. Metformin slows the development of cyst formation and fibrosis with the activation of AMPK and inhibition of signaling cascades responsible for cellular proliferation and fibrosis in the liver of PCK rats.NEW & NOTEWORTHYThis study indicates that metformin, an indirect AMPK activator slows liver cyst formation and fibrosis in PLD rat model. Metformin attenuates excessive cell proliferation in the liver with the inactivation of mTOR and ERK pathways. Metformin also reduces the expression of proteins responsible for cystic fluid secretion and liver fibrosis. Metformin and AMPK activators may be potent drugs for polycystic liver disease.