Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that β-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid Arrb2 deficiency prevented the development of MASH in mice. Further study showed that β-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid β-arrestin 2 depletion may be a potential approach for MASH.

中文翻译：

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髓样 β-arrestin 2 耗竭通过巨噬细胞的代谢重编程减轻代谢功能障碍相关的脂肪性肝炎


巨噬细胞介导的炎症与代谢功能障碍相关脂肪性肝炎 （MASH） 的发病机制有关;然而，调节巨噬细胞活化的免疫代谢程序仍不清楚。β-arrestin 2 是一种多功能衔接蛋白，在骨髓组织和巨噬细胞中高度表达，并参与代谢紊乱。在这里，我们观察到 β-arrestin 2 表达在 MASH 患者的肝脏巨噬细胞和循环单核细胞中与健康对照相比显著增加，并且与代谢功能障碍相关脂肪性肝病 （MASLD） 的严重程度呈正相关。整体或骨髓 Arrb2 缺陷阻止了小鼠 MASH 的发展。进一步研究表明，β-arrestin 2 作为衔接蛋白，促进免疫反应基因 1 （IRG1） 的泛素化，以防止巨噬细胞中衣康酸盐的产生增加，从而导致琥珀酸脱氢酶活性增强，从而促进线粒体活性氧的释放和 M1 极化。髓系 β-arrestin 2 耗竭可能是 MASH 的一种潜在方法。