Liver fibrosis is a common consequence of chronic liver diseases involved with the activation of hepatic stellate cells (HSCs) and endoplasmic reticulum (ER) stress. Irisin is a small polypeptide hormone that shows beneficial effects on metabolic disorders. The current study aimed to investigate the biological function of irisin on hepatic fibrosis. A mouse model of carbon tetrachloride (CCl 4 )-induced hepatic fibrosis was established. CCl 4 -treated mice showed elevated serum levels of AST and ALT, increased collagen accumulation, induced ER stress, and upregulated expressions of pro-fibrotic proteins in the liver compared to the controls. The administration of irisin, however, ameliorated CCl 4 -induced hepatic fibrosis in both cultured HSCs and mice. PKR-like ER kinase (PERK) is a key component of the ER stress-associated signaling pathway. We found that irisin treatment improved the stability of heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) via regulating the phosphorylation of PERK in mouse livers and isolated HSCs. Also, the knockdown of HNRNPA1 eliminated the hepatoprotective effects of irisin on hepatic fibrosis and ER stress. In summary, this study showed that irisin alleviated ER stress and hepatic fibrosis by inhibiting PERK-mediated HNRNPA1 destabilization, suggesting that irisin may represent a promising therapeutic strategy for patients with liver fibrosis.

中文翻译：

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鸢尾素通过抑制肝星状细胞中 PERK 介导的 HNRNPA1 不稳定来改善内质网应激和肝纤维化

肝纤维化是慢性肝病的常见后果，涉及肝星状细胞 (HSC) 的激活和内质网 (ER) 应激。鸢尾素是一种小的多肽激素，对代谢紊乱显示出有益的作用。目前的研究旨在研究鸢尾素对肝纤维化的生物学功能。建立四氯化碳（CCl 4 ）诱导的肝纤维化小鼠模型。与对照相比，CCl 4 处理的小鼠表现出升高的AST和ALT血清水平、增加的胶原积累、诱导的ER应激和上调肝中促纤维化蛋白的表达。然而，鸢尾素的给药改善了培养的 HSC 和小鼠中 CCl 4 诱导的肝纤维化。PKR 样内质网激酶 (PERK) 是内质网应激相关信号通路的关键组成部分。我们发现鸢尾素处理通过调节小鼠肝脏和分离的 HSC 中 PERK 的磷酸化来提高异质核糖核蛋白 A1 (HNRNPA1) 的稳定性。此外，HNRNPA1 的敲低消除了鸢尾素对肝纤维化和内质网应激的保肝作用。总之，这项研究表明，鸢尾素通过抑制 PERK 介导的 HNRNPA1 不稳定来减轻内质网应激和肝纤维化，表明鸢尾素可能代表了肝纤维化患者的一种有前途的治疗策略。