Protective Role of Hepassocin against Hepatic Endoplasmic Reticulum Stress in Mice.
Protective Role of Hepassocin against Hepatic Endoplasmic Reticulum Stress in Mice.
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DOI：
10.3390/ijms232113325
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发表时间：
2022-11-01
影响因子：
5.6
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中科院分区：
文献类型：
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肝蛋白酶（HPS）是一种具有多种生理功能的肝因子。HPS参与的一些生物学过程与内质网应激密切相关，但其在内质网应激调节中的作用尚不清楚。在这里，我们证明了HPS转录是由蛋白激酶rna样ER激酶(PERK)/激活转录因子4 （ATF4）级联在肝细胞内质网应激下诱导的。此外，禁食/再喂养也能诱导小鼠肝脏中HPS的表达。在体外实验中，HPS的缺失使肝细胞对内质网应激相关的细胞毒性敏感，而HPS治疗改变了这些表型。HPS缺乏加剧了体内禁食/再摄食诱导的内质网应激。在注射了tunicamycin （TM）的小鼠中，初步给药HPS可以改善肝脂肪变性、细胞死亡和炎症。即使在TM处理后注射HPS蛋白，也能观察到HPS的改善。此外，内质网应激抑制剂可减轻蛋氨酸和胆碱缺乏（MCD）饮食喂养的hps缺陷小鼠的脂肪性肝炎。这些结果表明，HPS保护肝细胞免受生理性和病理性内质网应激，HPS信号失活加剧内质网应激可能是驱动脂肪性肝炎发展的新机制。HPS对肝细胞内质网应激的保护机制与调节内质网钙处理和抑制内质网钙内流释放有关。总之，我们的研究结果表明，HPS可能以负反馈方式调节肝脏内质网应激，保护肝细胞免受内质网应激相关损伤。HPS有潜力成为治疗内质网应激相关肝损伤的候选药物。
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 HPS 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.
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影响因子：
4.6
作者：
Kim KH;Kim SH;Han DH;Jo YS;Lee YH;Lee MS
通讯作者：
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通讯作者：
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