GPR120 induces regulatory dendritic cells by inhibiting HK2-dependent glycolysis to alleviate fulminant hepatic failure.
GPR120 induces regulatory dendritic cells by inhibiting HK2-dependent glycolysis to alleviate fulminant hepatic failure.
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GPR120通过抑制HK2依赖性糖酵解诱导调节性树突状细胞缓解暴发性肝衰竭
DOI：
10.1038/s41419-021-04394-0
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发表时间：
2021-12-16
影响因子：
9
通讯作者：
Jin M
中科院分区：
文献类型：
--
作者：
Yu H;Yang W;Huang J;Miao X;Wang B;Ren X;Gu Y;Wang Q;Ding X;Guo X;Qian F;Zhang Y;Xu H;Zheng L;Jin M
暴发性肝衰竭（FHF）是一种潜在的致命性肝脏疾病，与肝内炎症细胞浸润有关。GPR120作为多不饱和长链脂肪酸受体，具有调节细胞分化、增殖、代谢和免疫应答等功能。然而，GPR120是否参与FHF仍不清楚。UsingPropionibacterium曼秀雷敦(P。在小鼠FHF中，我们发现使用药物激动剂干扰GPR120活性可以减轻小鼠肝损伤的严重程度和FHF的死亡率，而缺乏GPR120则加重了疾病。GPR120激活可有效缓解FHF，导致辅助性T细胞（Th） 1应答降低和调节性T细胞（Tregs）扩增。有趣的是，GPR120激动剂并不直接靶向T细胞，而是在FHF小鼠的肝脏中显著诱导CD11c+MHC iilow cd80low cd86low - regulatory dc。发现GPR120限制hif -1α依赖性糖酵解。GPR120拮抗剂或缺失引起的HIF-1α稳定性增强可以通过抑制ERK或激活AMPK来减弱。通过对临床FHF的分析，我们进一步证实GPR120的激活与患者病情严重程度呈负相关。我们的研究结果表明，激活GPR120在FHF中具有治疗潜力。使用激动剂或游离脂肪酸（FFAs）靶向GPR120的策略可能代表一种治疗FHF的新方法。
Fulminant hepatic failure (FHF) is a potentially fatal liver disease that is associated with intrahepatic infiltration of inflammatory cells. As the receptor of polyunsaturated long chain fatty acids, GPR120 can regulate cell differentiation, proliferation, metabolism, and immune response. However, whether GPR120 is involved in FHF remains unknown. UsingPropionibacterium acnes(P. acnes)-primed, LPS-induced FHF in mice, we found that interference with GPR120 activity using pharmacological agonist attenuated the severity of the liver injury and mortality of FHF in mice, while a lack of GPR120 exacerbated the disease. GPR120 activation potently alleviated FHF and led to decreased T helper (Th) 1 cell response and expansion of regulatory T cells (Tregs). Interestingly, GPR120 agonist didn’t directly target T cells, but dramatically induced a distinct population of CD11c+MHC IIlowCD80lowCD86lowregulatory DCs in the livers of FHF mice. GPR120 was found to restrict HIF-1α-dependent glycolysis. The augmented HIF-1α stabilization caused by GPR120 antagonism or deletion could be attenuated by the inhibition of ERK or by the activation of AMPK. Through the analysis of the clinical FHF, we further confirmed the activation of GPR120 was negatively associated with the severity in patients. Our findings indicated that GPR120 activation has therapeutic potential in FHF. Strategies to target GPR120 using agonists or free fatty acids (FFAs) may represent a novel approach to FHF treatment.
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