巨噬细胞MerTK促进非酒精性脂肪肝炎（NASH）的纤维化，这一成果由美国哥伦比亚大学Ira Tabas、Bishuang Cai等研究人员合作取得。2019年12月12日，国际知名学术期刊《细胞—代谢》在线发表了这一成果。

 

研究人员发现，在NASH小鼠中靶向全部的或髓样的巨噬细胞c-mer酪氨酸激酶（MerTK）可以降低肝纤维化，与人类遗传数据一致。此外，在脂肪变性至NASH过渡期间，肝脏巨噬细胞中ADAM金属肽酶结构域17蛋白（ADAM17）介导的MerTK切割减少，此外具有切割抗性的MerTK突变体小鼠NASH纤维化增加。巨噬细胞MerTK促进ERK-TGFβ1通路，该通路激活肝星状细胞（HSC）并诱导肝纤维化。

 

这些数据提供了关于肝巨噬细胞在NASH纤维化中作用的见解，并提供了MERTK作为NASH纤维化遗传危险因素的可能的机制。

 

据介绍，NASH逐渐成为慢性肝病的主要原因。但是，由于对NASH纤维化（这是由HSC激活介导的）机制的不完全了解，治疗选择受到了限制。在人类中，人类基因研究表明，编码MerTK受体的MERTK亚型变异提供了针对肝纤维化的保护作用，但其机制仍然未知。

 

附：英文原文

 

Title: Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis

 

Author: Bishuang Cai, Paola Dongiovanni, Kathleen E. Corey, Xiaobo Wang, Igor O. Shmarakov, Ze Zheng, Canan Kasikara, Viralkumar Davra, Marica Meroni, Raymond T. Chung, Carla V. Rothlin, Robert F. Schwabe, William S. Blaner, Raymond B. Birge, Luca Valenti, Ira Tabas

 

Issue&Volume: December 12, 2019

 

Abstract: Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liverdisease. However, therapeutic options are limited by incomplete understanding of themechanisms of NASH fibrosis, which is mediated by activation of hepatic stellate cells(HSCs). In humans, human genetic studies have shown that hypomorphic variations inMERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protectionagainst liver fibrosis, but the mechanisms remain unknown. We now show that holo-or myeloid-specific Mertk targeting in NASH mice decreases liver fibrosis, congruent with the human geneticdata. Furthermore, ADAM metallopeptidase domain 17 (ADAM17)-mediated MerTK cleavagein liver macrophages decreases during steatosis to NASH transition, and mice witha cleavage-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotesan ERK-TGFβ1 pathway that activates HSCs and induces liver fibrosis. These data provideinsights into the role of liver macrophages in NASH fibrosis and provide a plausiblemechanism underlying MERTK as a genetic risk factor for NASH fibrosis.

 

DOI: 10.1016/j.cmet.2019.11.013

 

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30620-5