Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding 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, encoding 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 metallopeptidase domain 17 (ADAM17)-mediated MerTK cleavage in liver macrophages decreases during steatosis to NASH transition, and mice with a cleavage-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotes an ERK-TGFβ1 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.

中文翻译：

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巨噬细胞 MerTK 促进非酒精性脂肪性肝炎的肝纤维化。

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，由于对 NASH 纤维化机制的不完全了解，治疗选择受到限制，NASH 纤维化由肝星状细胞 (HSC) 的激活介导。在人类中，人类遗传研究表明，编码巨噬细胞 c-mer 酪氨酸激酶 (MerTK) 受体的 MERTK 的亚形变异提供了防止肝纤维化的保护，但其机制仍然未知。我们现在表明 NASH 小鼠中的全血或骨髓特异性 Mertk 靶向可减少肝纤维化，这与人类遗传数据一致。此外，肝脏巨噬细胞中由 ADAM 金属肽酶结构域 17 (ADAM17) 介导的 MerTK 切割在脂肪变性向 NASH 过渡期间减少，并且具有抗切割 MerTK 突变体的小鼠 NASH 纤维化增加。巨噬细胞 MerTK 促进 ERK-TGFβ1 通路激活 HSC 并诱导肝纤维化。这些数据提供了对肝巨噬细胞在 NASH 纤维化中的作用的见解，并为 MERTK 作为 NASH 纤维化的遗传风险因素提供了一个合理的机制。