p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in Mice.
p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in Mice.
复制标题
DOI：
10.1016/j.jcmgh.2021.09.001
复制
发表时间：
2022
影响因子：
7.2
通讯作者：
De Toni EN
中科院分区：
文献类型：
--
作者：
Reiter FP;Ye L;Ofner A;Schiergens TS;Ziesch A;Brandl L;Ben Khaled N;Hohenester S;Wimmer R;Artmann R;He Y;Lee SML;Mayr D;Zhang C;Gerbes AL;Mayerle J;Denk G;De Toni EN
慢性肝病（CLD）进展为肝硬化和肝癌是全球发病率和死亡率的主要原因。当CLD的病因治疗不可用或失败时，能够抑制肝纤维化进展的治疗方案尚未确定。我们研究了丝氨酸/苏氨酸激酶p70核糖体蛋白S6激酶（p70S6K）作为肝星状细胞（hsc）纤维化发生的检查点和治疗肝纤维化的靶点的作用。免疫组化检测p70S6K在肝切除标本中的表达。体外实验采用野生型或p70S6K - / -小鼠的原代人或鼠造血干细胞以及LX-2细胞。使用特异性小干扰RNA或CEP-1347沉默或抑制p70S6K，并在活力、收缩和迁移试验、荧光活化细胞分选和Western blot中评估其功能相关性。这些结果通过野生型和p70S6K - / -小鼠的体内纤维形成化学模型得到了验证。p70S6K的表达在人肝硬化与非肝硬化肝组织中显著增加，并通过激活原代人hsc在体外逐渐增加。相反，在不同的模型中，p70S6K诱导HSC的纤维化活化，包括在HSC细胞系中基于小干扰rna的p70S6K沉默，p70S6K - / -细胞实验，以及CEP-1347对p70S6K的药理学抑制。这些发现在体内得到了验证，p70S6K - / -小鼠暴露于CCl4后纤维化明显减少。我们将p70S6K作为体外和体内纤维形成的检查点，将CEP-1347作为可以安全用于长期治疗的潜在治疗选择。
Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis. Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K–/– mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K–/– mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA–based silencing of p70S6K in HSC lines, experiments with p70S6K–/– cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K–/– mice developed significantly less fibrosis upon exposure to CCl4. We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment.
登录
查看更多内容
影响因子：
4.2
作者：
Sadeghi N;Gerber DE
通讯作者：
Gerber DE
影响因子：
8.6
作者：
Schwid, Steven R.;Bausch, Janice;Shoulson, Ira
通讯作者：
Shoulson, Ira
影响因子：
1.2
作者：
Lee, Serene M. L.;Schelcher, Celine;Thasler, Wolfgang E.
通讯作者：
Thasler, Wolfgang E.
影响因子：
29.4
作者：
Marra, F;Gentilini, A;Gentilini, P
通讯作者：
Gentilini, P
影响因子：
29.4
作者：
Svegliati-Baroni, G;Ridolfi, F;Moshage, H
通讯作者：
Moshage, H