Hepatic inflammation is culpable for the evolution of asymptomatic steatosis to nonalcoholic steatohepatitis (NASH). Hepatic inflammation results from abnormal macrophage activation. We found that FoxO1 links overnutrition to hepatic inflammation by regulating macrophage polarization and activation. FoxO1 was upregulated in hepatic macrophages, correlating with hepatic inflammation, steatosis, and fibrosis in mice and patients with NASH. Myeloid cell conditional FoxO1 knockout skewed macrophage polarization from proinflammatory M1 to the antiinflammatory M2 phenotype, accompanied by a reduction in macrophage infiltration in liver. These effects mitigated overnutrition-induced hepatic inflammation and insulin resistance, contributing to improved hepatic metabolism and increased energy expenditure in myeloid cell FoxO1–knockout mice on a high-fat diet. When fed a NASH-inducing diet, myeloid cell FoxO1–knockout mice were protected from developing NASH, culminating in a reduction in hepatic inflammation, steatosis, and fibrosis. Mechanistically, FoxO1 counteracts Stat6 to skew macrophage polarization from M2 toward the M1 signature to perpetuate hepatic inflammation in NASH. FoxO1 appears to be a pivotal mediator of macrophage activation in response to overnutrition and a therapeutic target for ameliorating hepatic inflammation to stem the disease progression from benign steatosis to NASH.

中文翻译：

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骨髓 FoxO1 耗竭可减轻肝脏炎症并预防非酒精性脂肪性肝炎

肝脏炎症是无症状脂肪变性演变为非酒精性脂肪性肝炎 (NASH) 的罪魁祸首。肝脏炎症是由异常的巨噬细胞活化引起的。我们发现 FoxO1 通过调节巨噬细胞极化和活化将营养过剩与肝脏炎症联系起来。FoxO1 在肝巨噬细胞中上调，与小鼠和 NASH 患者的肝脏炎症、脂肪变性和纤维化相关。骨髓细胞条件性 FoxO1 敲除使巨噬细胞极化从促炎 M1 向抗炎 M2 表型倾斜，伴随着肝脏中巨噬细胞浸润的减少。这些作用减轻了营养过剩引起的肝脏炎症和胰岛素抵抗，有助于改善高脂饮食的骨髓细胞 FoxO1 敲除小鼠的肝脏代谢和增加能量消耗。当喂食 NASH 诱导饮食时，骨髓细胞 FoxO1 基因敲除小鼠免受 NASH 的发展，最终导致肝脏炎症、脂肪变性和纤维化减少。从机制上讲，FoxO1 抵消 Stat6 以使巨噬细胞极化从 M2 向 M1 特征倾斜，从而使 NASH 中的肝脏炎症持续存在。FoxO1 似乎是巨噬细胞活化以应对营养过剩的关键介质，也是缓解肝脏炎症以阻止疾病从良性脂肪变性发展为 NASH 的治疗靶点。从机制上讲，FoxO1 抵消 Stat6 以使巨噬细胞极化从 M2 向 M1 特征倾斜，从而使 NASH 中的肝脏炎症持续存在。FoxO1 似乎是巨噬细胞活化以应对营养过剩的关键介质，也是缓解肝脏炎症以阻止疾病从良性脂肪变性发展为 NASH 的治疗靶点。从机制上讲，FoxO1 抵消 Stat6 以使巨噬细胞极化从 M2 向 M1 特征倾斜，从而使 NASH 中的肝脏炎症持续存在。FoxO1 似乎是巨噬细胞活化以应对营养过剩的关键介质，也是缓解肝脏炎症以阻止疾病从良性脂肪变性发展为 NASH 的治疗靶点。