A new <scp>liver regeneration</scp> molecular mechanism involving hepatic stellate cells, Kupffer cells, and <scp>glucose‐regulated</scp> protein 78 as a new hepatotrophic factor
A new <scp>liver regeneration</scp> molecular mechanism involving hepatic stellate cells, Kupffer cells, and <scp>glucose‐regulated</scp> protein 78 as a new hepatotrophic factor
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一种新的<scp>肝再生</scp>分子机制，涉及肝星状细胞、库普弗细胞和作为新肝营养因子的<scp>葡萄糖调节</scp>蛋白78
DOI：
10.1002/jhbp.1183
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发表时间：
2022
影响因子：
3
通讯作者：
Shirabe Ken
中科院分区：
文献类型：
--
作者：
Hagiwara Kei;Harimoto Norifumi;Yamanaka Takahiro;Ishii Norihiro;Yokobori Takehiko;Tsukagoshi Mariko;Watanabe Akira;Araki Kenichiro;Yoshizumi Tomoharu;Shirabe Ken
背景/目的为了克服肝衰竭，我们着重于通过激活肝星状细胞（HSC）和枯否细胞（KCs）来研究肝再生机制。已知HSC分泌的Mac-2结合蛋白聚糖异构体（M2 BPGi）激活纤维化肝脏中的KC。然而，其对肝切除术后HSC/M2 BPG 1/KCs轴的肝再生的重要性仍然未知。本研究的目的是阐明HSC来源的M2 BPGi是否可以激活肝切除术后的KCs，并阐明肝再生的新分子机制。MethodsWe检查了M2 BPGi对人肝细胞和KCs的影响，并使用蛋白质组学探索M2 BPGi激活的KCs的分泌因子。此外，在体外和小鼠肝切除模型中检测了M2 BPGi相关分泌蛋白之一葡萄糖调节蛋白78（GRP 78）对肝再生的影响。结果M2 BPGi对肝细胞没有促进作用，但促进了KC中GRP 78的产生。KC驱动的GRP 78促进肝细胞增殖。GRP 78给药促进了70%肝切除术后的肝再生，并提高了小鼠90%肝切除术后的存活率。结论M2 BPGi激活的KCs分泌GRP 78，促进了肝再生，并提高了致死小鼠模型的存活率。我们的数据表明，新的肝营养因子GRP 78可能是一个有前途的治疗工具，致死性肝衰竭。
Background/PurposeTo overcome liver failure, we focused on liver regeneration mechanisms by the activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs). It is known that the HSC‐secreted Mac‐2‐binding protein glycan isomer (M2BPGi) activates KC in the fibrotic liver. However, its importance for liver regeneration of the HSCs/M2BPGi/KCs axis after hepatectomy is still unknown. The aim of this study was to clarify whether the HSC‐derived M2BPGi can activate KCs after hepatectomy, and elucidate the new molecular mechanism of liver regeneration.MethodsWe examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi‐activated KCs using proteomics. Furthermore, the effect on liver regeneration of glucose‐regulated protein 78 (GRP78) as one of the M2BPGi‐related secreted proteins was examined in vitro and in murine hepatectomy models.ResultsAlthough M2BPGi had no hepatocyte‐promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KC‐driven GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration after 70% hepatectomy and increased the survival rate after 90% hepatectomy in mice.ConclusionsThe M2BPGi‐activated KCs secrete GRP78, which facilitates liver regeneration and improves the survival in a lethal mice model. Our data suggest that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure.