Adipocyte Death Preferentially Induces Liver Injury and Inflammation Through the Activation of Chemokine (C-C Motif) Receptor 2-Positive Macrophages and Lipolysis
Adipocyte Death Preferentially Induces Liver Injury and Inflammation Through the Activation of Chemokine (C-C Motif) Receptor 2-Positive Macrophages and Lipolysis
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DOI：
10.1002/hep.30525
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发表时间：
2019-05-01
期刊：
影响因子：
13.5
通讯作者：
Gao, Bin
中科院分区：
文献类型：
--
作者：
Kim, Seung-Jin;Feng, Dechun;Gao, Bin
脂肪细胞死亡发生在各种病理生理条件下，包括肥胖和饮酒，并可引发器官损伤，特别是在肝脏中，但其潜在机制仍不清楚。为了探索这些机制，我们通过在脂肪细胞上过表达人CD 59（hCD 59）（脂肪细胞特异性hCD 59转基因小鼠）开发了诱导性脂肪细胞死亡的小鼠模型。用中间溶素（ILY）注射这些小鼠，该中间溶素（ILY）通过结合hCD 59而非小鼠CD 59而快速溶解hCD 59表达细胞，导致脂肪细胞急性选择性死亡、脂肪巨噬细胞浸润和血清游离脂肪酸（FFA）水平升高。ILY注射还导致对多个器官的继发性损伤，在肝脏中观察到最强的损伤，伴有炎症和肝巨噬细胞活化。在机制上，急性脂肪细胞死亡升高肾上腺素和去甲肾上腺素水平，并以趋化因子（C-C基序）受体2阳性（CCR 2（+））巨噬细胞依赖性方式激活脂肪组织中的脂解途径，随后是肝脏中的FFA释放和脂毒性。此外，急性脂肪细胞死亡引起肝CCR 2（+）巨噬细胞活化和浸润，进一步加重肝损伤。结论：脂肪细胞死亡主要诱导肝损伤和炎症，这可能是由于肝细胞对脂毒性的上级敏感性和肝脏中大量的巨噬细胞。
Adipocyte death occurs under various physiopathological conditions, including obesity and alcohol drinking, and can trigger organ damage particularly in the liver, but the underlying mechanisms remain obscure. To explore these mechanisms, we developed a mouse model of inducible adipocyte death by overexpressing the human CD59 (hCD59) on adipocytes (adipocyte-specific hCD59 transgenic mice). Injection of these mice with intermedilysin (ILY), which rapidly lyses hCD59 expressing cells exclusively by binding to the hCD59 but not mouse CD59, resulted in the acute selective death of adipocytes, adipose macrophage infiltration, and elevation of serum free fatty acid (FFA) levels. ILY injection also resulted in the secondary damage to multiple organs with the strongest injury observed in the liver, with inflammation and hepatic macrophage activation. Mechanistically, acute adipocyte death elevated epinephrine and norepinephrine levels and activated lipolysis pathways in adipose tissue in a chemokine (C-C motif) receptor 2-positive (CCR2(+)) macrophage-dependent manner, which was followed by FFA release and lipotoxicity in the liver. Additionally, acute adipocyte death caused hepatic CCR2(+) macrophage activation and infiltration, further exacerbating liver injury. Conclusion: Adipocyte death predominantly induces liver injury and inflammation, which is probably due to the superior sensitivity of hepatocytes to lipotoxicity and the abundance of macrophages in the liver.