A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of MET.
A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of MET.
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NASH 的新型人源化模型及其使用 META4（MET 的有效激动剂）的治疗。
DOI：
10.1016/j.jcmgh.2021.10.007
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发表时间：
2022
影响因子：
7.2
通讯作者：
Zarnegar R
中科院分区：
文献类型：
--
作者：
Ma J;Tan X;Kwon Y;Delgado ER;Zarnegar A;DeFrances MC;Duncan AW;Zarnegar R
非酒精性脂肪肝是肝功能障碍的常见原因，现在是全球流行病。这种疾病可以进展为称为非酒精性脂肪性肝炎（NASH）和终末期肝病的高级形式。目前，NASH发病机制的分子基础知之甚少，并且不存在治疗NASH的有效疗法。这些缺点是由于缺乏与人类直接相关的NASH实验模型。我们使用人源化肝脏嵌合小鼠在相关模型中研究非酒精性脂肪性肝病。我们进行了组织学，生物化学和分子方法，包括RNA-Seq。为了比较，我们使用了并行的人NASH样品。在此，我们描述了一个“人源化”的NASH模型，使用人肝细胞移植到富马酰乙酰乙酸水解酶缺陷的小鼠。一旦喂食高脂肪饮食，这些小鼠忠实地发展NAFLD，在组织学、细胞、生物化学和分子水平上再现人类NASH。我们的RNA-Seq分析发现，在人源化和人NASH肝脏中，控制肝脏稳态的各种重要信号传导途径都被严重失调。值得注意的是，我们做出了新的发现，即肝细胞生长因子（HGF）功能在人和人源化NASH中在几个水平上受损，包括称为NK 1/NK 2的HGF拮抗剂的表达显著增加和HGF激活剂的显著减少。基于这些观察结果，我们产生了一种有效的、人类特异性的和稳定的人MET激动剂，我们将其命名为META 4（Metaphor），并将其用于人源化NASH模型中以恢复HGF功能。我们的研究表明，人源化NASH模型重现了人类NASH，并发现HGF-MET功能在这种疾病中受损。我们表明，在人源化NASH模型中，通过META 4治疗恢复HGF-MET功能可改善NASH并恢复正常肝功能。我们的研究结果表明，HGF-MET信号通路是肝脏稳态的主要调节因子。
Nonalcoholic fatty liver disease is a frequent cause of hepatic dysfunction and is now a global epidemic. This ailment can progress to an advanced form called nonalcoholic steatohepatitis (NASH) and end-stage liver disease. Currently, the molecular basis of NASH pathogenesis is poorly understood, and no effective therapies exist to treat NASH. These shortcomings are due to the paucity of experimental NASH models directly relevant to humans. We used chimeric mice with humanized liver to investigate nonalcoholic fatty liver disease in a relevant model. We carried out histologic, biochemical, and molecular approaches including RNA-Seq. For comparison, we used side-by-side human NASH samples. Herein, we describe a “humanized” model of NASH using transplantation of human hepatocytes into fumarylacetoacetate hydrolase-deficient mice. Once fed a high-fat diet, these mice develop NAFLD faithfully, recapitulating human NASH at the histologic, cellular, biochemical, and molecular levels. Our RNA-Seq analyses uncovered that a variety of important signaling pathways that govern liver homeostasis are profoundly deregulated in both humanized and human NASH livers. Notably, we made the novel discovery that hepatocyte growth factor (HGF) function is compromised in human and humanized NASH at several levels including a significant increase in the expression of the HGF antagonists known as NK1/NK2 and marked decrease in HGF activator. Based on these observations, we generated a potent, human-specific, and stable agonist of human MET that we have named META4 (Metaphor) and used it in the humanized NASH model to restore HGF function. Our studies revealed that the humanized NASH model recapitulates human NASH and uncovered that HGF-MET function is impaired in this disease. We show that restoring HGF-MET function by META4 therapy ameliorates NASH and reinstates normal liver function in the humanized NASH model. Our results show that the HGF-MET signaling pathway is a dominant regulator of hepatic homeostasis.
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影响因子：
46.9
作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
通讯作者：
Grompe, Markus
DOI：
10.2183/pjab.86.588
发表时间：
2010
期刊：
Proceedings of the Japan Academy. Series B, Physical and biological sciences
影响因子：
--
作者：
Nakamura T;Mizuno S
通讯作者：
Mizuno S
影响因子：
5.3
作者：
Kessler, John A.;Smith, A. Gordon;Cha, Bong-Soo;Choi, Sung Hee;Wymer, James;Shaibani, Aziz;Ajroud-Driss, Senda;Vinik, Aaron
通讯作者：
Vinik, Aaron
影响因子：
11.4
作者：
LOKKER, NA;MARK, MR;GODOWSKI, PJ
通讯作者：
GODOWSKI, PJ
DOI：
10.1111/j.1440-1746.2007.05111.x
发表时间：
2008-08-01
影响因子：
4.1
作者：
Kiyama, Shigeru;Yamada, Takuya;Takemura, Hirofumi
通讯作者：
Takemura, Hirofumi