Cathepsin L-deficiency enhances liver regeneration after partial hepatectomy
Cathepsin L-deficiency enhances liver regeneration after partial hepatectomy
复制标题
组织蛋白酶 L 缺乏可增强部分肝切除术后的肝再生
DOI：
10.1016/j.lfs.2019.02.040
复制
发表时间：
2019
期刊：
影响因子：
6.1
通讯作者：
Watanabe Sumio
中科院分区：
文献类型：
--
作者：
Sato Toshifumi;Yamashina Shunhei;Izumi Kosuke;Ueno Takashi;Koike Masato;Ikejima Kenichi;Peters Christoph;Watanabe Sumio
目的：组织蛋白酶L（Cathepsin L，Ctsl）在溶酶体和自噬蛋白水解中起重要作用。以往的研究表明，部分肝切除术（PH）减少组织蛋白酶在肝脏中的生物合成，随后抑制肝再生过程中的溶酶体和自噬蛋白水解。相反，据报道，自噬缺陷抑制肝再生。因此，本研究的目的是，以确定是否Ctsl缺陷影响肝再生后PH.Methods：70%的PH进行雄性Ctsl缺陷型小鼠（Ctsl-/-）和野生型同窝仔（Ctsl +/+）后PH。小鼠被处死，并测量整个剩余的肝脏湿重。对肝脏切片进行溴脱氧尿苷（BrdU）免疫染色。Western blot检测cyclin D1、p62、LC-3、Nrf2、cleaved-Notch1、Hes1的表达。结果：与野生型小鼠相比，Ctsl-/-小鼠在70%PH后，肝脏质量在5d内显著恢复。与野生型小鼠相比，Ctsl缺乏增强了PH后BrdU阳性细胞率和细胞周期蛋白D1表达的增加。另一方面，Ctsl-/-小鼠PH后p62、cleaved-Notch1和Hes1的表达上调。此外，PH后Ctsl-/-小鼠核中Nrf2的蛋白水平和肝脏中NQO1的mRNA表达也上调。结论：这些发现表明，由于Ctsl的缺失导致的p62的积累通过激活Nrf2-Notchl信号传导在肝再生中起重要作用。因此，Ctsl可能成为治疗肝再生障碍的新靶点。
Aim: Cathepsin L (Ctsl) plays a pivotal role in lysosomal and autophagic proteolysis. Previous investigations revealed that partial hepatectomy (PH) decreases biosynthesis of cathepsins in liver, followed by suppression of lysosomal and autophagic proteolysis during liver regeneration. Conversely, it was reported that autophagy-deficiency suppressed liver regeneration. Thus, the purpose of this study is to determine if Ctsl deficiency affects liver regeneration after PH. Methods: 70% of PH was performed in male Ctsl-deficient mice (Ctsl-/-) and wild-type littermates (Ctsl+/+) after PH. Mice were sacrificed and wet weight of the whole remaining liver was measured. Bromodeoxyuridine (BrdU)-immunostaining of liver sections was performed. Expression of cyclin D1, p62, LC-3, Nrf2, cleaved-Notch1, Hes1 was evaluated by western blot analysis. NQO1 mRNA expression was measured by realtime-PCR.Results: After a 70% of PH, the liver mass was significantly restored within 5days in Ctsl-/-mice compared to wild-type. Ctsl-deficiency enhanced the increases in both the rate of BrdU-positive cells and cyclin D1 expression after PH more than wild-type mice. On the other hand, Ctsl-deficiency upregulated p62, cleaved-Notch1 and Hes1 expression after PH. Moreover, the protein level of Nrf2 in the nucleus and mRNA expression of NQO1 in the liver after PH was also up-regulated in Ctsl-/-mice. Conclusions: These findings suggest that accumulation of p62 due to loss of Ctsl plays an important role in liver regeneration through activation of Nrf2-Notch1 signaling. Taken together, Ctsl might be a new therapeutic target on disorder of liver regeneration.