Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
Beijing Institute of Radiation Medicine, Beijing 100850, China.
Int J Mol Sci. 2022 Nov 1;23(21):13325. doi: 10.3390/ijms232113325.
Hepassocin (HPS) is a hepatokine that has multiple proposed physiological functions. Some of the biological processes in which it is involved are closely related to endoplasmic reticulum (ER) stress, but the role of HPS in the regulation of ER stress remains unclear. Here, we demonstrated that transcription is induced by the protein kinase RNA-like ER kinase (PERK)/activating transcription factor 4 (ATF4) cascade upon ER stress in hepatocytes. Additionally, fasting/refeeding also induced HPS expression in mice liver. The loss of HPS sensitizes hepatocytes to ER stress-related cytotoxicity in vitro, whereas HPS treatment altered these phenotypes. HPS deficiency exacerbates fasting/refeeding-induced ER stress in vivo. The preliminary administration of HPS ameliorates liver steatosis, cell death, and inflammation in mice injected with tunicamycin (TM). The improvement of HPS can be observed even if HPS protein is injected after TM treatment. Furthermore, the administration of an ER stress inhibitor alleviated steatohepatitis in methionine- and choline-deficient (MCD) diet-fed HPS-deficient mice. These results suggest that HPS protects hepatocytes from physiological and pathological ER stress, and that the inactivation of HPS signaling aggravating ER stress may be a novel mechanism that drives the development of steatohepatitis. The protective mechanism of HPS against ER stress in hepatocytes was associated with the regulation of ER calcium handling, and the suppression of calcium influx release from ER upon stressor treatment. Collectively, our findings indicate that HPS may act in a negative feedback fashion to regulate hepatic ER stress and protect hepatocytes from ER stress-related injury. HPS has the potential to be a candidate drug for the treatment of ER stress-related liver injury.
Hepassocin (HPS) 是一种细胞因子，具有多种推测的生理功能。它参与的一些生物学过程与内质网 (ER) 应激密切相关，但 HPS 在调节 ER 应激中的作用尚不清楚。在这里，我们证明在肝细胞中，内质网应激诱导蛋白激酶 RNA 样内质网激酶 (PERK)/激活转录因子 4 (ATF4) 级联反应诱导 HPS 转录。此外，禁食/再喂养也诱导小鼠肝脏中 HPS 的表达。HPS 的缺失使肝细胞对 ER 应激相关细胞毒性敏感，而 HPS 处理改变了这些表型。HPS 缺乏加剧了体内禁食/再喂养诱导的 ER 应激。HPS 的初步给药可改善注射衣霉素 (TM) 的小鼠肝脂肪变性、细胞死亡和炎症。即使在 TM 处理后注射 HPS 蛋白，也可以观察到 HPS 的改善。此外，内质网应激抑制剂的给药可缓解蛋氨酸和胆碱缺乏 (MCD) 饮食喂养的 HPS 缺陷小鼠的脂肪性肝炎。这些结果表明，HPS 可保护肝细胞免受生理性和病理性 ER 应激，而 HPS 信号失活加剧 ER 应激可能是驱动脂肪性肝炎发展的新机制。HPS 对肝细胞 ER 应激的保护机制与 ER 钙处理的调节有关，以及应激处理时抑制 ER 钙内流和释放。总之，我们的研究结果表明，HPS 可能以负反馈的方式作用于调节肝内质网应激，保护肝细胞免受 ER 应激相关损伤。HPS 有可能成为治疗 ER 应激相关肝损伤的候选药物。
