Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis
Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis
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DOI：
10.1016/j.cmet.2019.11.013
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发表时间：
2020-02-04
期刊：
影响因子：
29
通讯作者：
Tabas, Ira
中科院分区：
文献类型：
--
作者：
Cai, Bishuang;Dongiovanni, Paola;Tabas, Ira
非酒精性脂肪性肝炎（NASH）正在成为慢性肝病的主要原因。然而，治疗选择受到对NASH纤维化机制的不完全理解的限制，NASH纤维化是由肝星状细胞（HSC）的活化介导的。在人类中，人类遗传学研究表明，MERTK中的亚型变异（编码巨噬细胞c-mer酪氨酸激酶（MerTK）受体）可提供抗肝纤维化的保护，但机制仍未知。我们现在表明，NASH小鼠中的全或骨髓特异性Mertk靶向可以减少肝纤维化，这与人类遗传数据一致。此外，在脂肪变性向NASH转变期间，肝脏巨噬细胞中ADAM金属肽酶结构域17（ADAM 17）介导的MerTK切割减少，并且具有抗切割年龄MerTK突变体的小鼠具有增加的NASH纤维化。巨噬细胞MerTK促进活化HSC并诱导肝纤维化的ERK-TG 931途径。这些数据为肝脏巨噬细胞在NASH纤维化中的作用提供了见解，并提供了MERTK作为NASH纤维化遗传风险因素的合理机制。
Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete under-standing of the mechanisms of NASH fibrosis, which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encod-ing the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against 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 genetic data. Furthermore, ADAM metallo-peptidase domain 17 (ADAM17)-mediated MerTK cleavage in liver macrophages decreases during steatosis to NASH transition, and mice with a cleav-age-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotes an ERK-TG931 pathway that activates HSCs and induces liver fibrosis. These data provide insights into the role of liver macrophages in NASH fibrosis and provide a plausible mechanism underlying MERTK as a genetic risk factor for NASH fibrosis.