Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis.
Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis.
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DOI：
10.1172/jci154333
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发表时间：
2022-07-15
影响因子：
15.9
通讯作者：
Dong, H. Henry
中科院分区：
文献类型：
--
作者：
Lee, Sojin;Usman, Taofeek O.;Yamauchi, Jun;Chhetri, Goma;Wang, Xingchun;Coudriet, Gina M.;Zhu, Cuiling;Gao, Jingyang;McConnell, Riley;Krantz, Kyler;Rajasundaram, Dhivyaa;Singh, Sucha;Piganelli, Jon;Ostrowska, Alina;Soto-Gutierrez, Alejandro;Monga, Satdarshan P.;Singhi, Aatur D.;Muzumdar, Radhika;Tsung, Allan;Dong, H. Henry
肝脏炎症是无症状脂肪变性发展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激活将营养过剩与肝脏炎症联系起来。FoxO1在肝脏巨噬细胞中上调，与小鼠和NASH患者的肝脏炎症、脂肪变性和纤维化相关。髓样细胞条件FoxO1敲除使巨噬细胞极化从促炎性M1向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诱导的肝脏炎症和胰岛素抵抗，有助于改善高脂肪饮食的骨髓细胞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，髓样细胞FoxO1敲除小鼠被保护免于发展NASH，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，使巨噬细胞从M2向M1的极化，从而使NASH的肝脏炎症永久化。FoxO1似乎是响应营养过剩的巨噬细胞活化的关键介质，并且是改善肝脏炎症以阻止疾病从良性脂肪变性进展为NASH的治疗靶点。
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.
影响因子：
4.5
作者：
Gong L;Li R;Ren W;Wang Z;Wang Z;Yang M;Zhang S
通讯作者：
Zhang S