Metabolic stress drives sympathetic neuropathy within the liver
Metabolic stress drives sympathetic neuropathy within the liver
复制标题
代谢应激导致肝脏内交感神经病变
DOI：
10.1016/j.cmet.2021.01.012
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发表时间：
2021-03-02
期刊：
影响因子：
29
通讯作者：
Yang, Jing
中科院分区：
文献类型：
--
作者：
Liu, Kaili;Yang, Lu;Yang, Jing
神经系统指导身体的新陈代谢，包括肝脏的新陈代谢。然而，在正常或代谢应激条件下肝脏的神经解剖结构仍有待明确评估。在这里，我们用先进的3D成像检查了小鼠、非人灵长类动物和人类肝脏中的神经分布。我们观察到，肝脏内的神经支配主要是交感神经，但不是副交感神经，输入。此外，我们发现在代谢挑战期间这种交感神经支配的深刻和可逆的损失。这种肝交感神经病变是由高脂饮食（HFD）条件下CD 11b（+）F4/80（+）免疫细胞产生的TNF α引起的。我们进一步证明了Sarm 1缺失减轻了HFD攻击小鼠的肝交感神经病变并改善了代谢参数。从机制上讲，交感神经递质去甲肾上腺素减弱了免疫细胞炎症，否则会触发肝细胞的胰岛素不敏感性。这些结果共同揭示了肝脏中先前未被认识到的具有代谢相关性的神经性事件。
The nervous system instructs the body's metabolism, including that in the liver. However, the neural anatomy of the liver under either normal or metabolically stressed conditions remains to be unequivocally assessed. Here, we examined neural distributions in the mouse, nonhuman primate, and human livers with advanced 3D imaging. We observed that neural innervations within the liver are predominantly sympathetic, but not para-sympathetic, inputs. Moreover, we discovered the profound and reversible loss of such sympathetic innervations during metabolic challenges. This hepatic sympathetic neuropathy was caused by TNF alpha derived from CD11b(+) F4/80(+) immune cells under high-fat-diet (HFD) condition. We further demonstrated that the Sarm1 deletion mitigated the hepatic sympathetic neuropathy and improved metabolic parameters in HFD-challenged mice. Mechanistically, the sympathetic neurotransmitter norepinephrine attenuated the immune-cell inflammation that would otherwise trigger the insulin insensitivity of hepatocytes. These results together reveal the previously unrecognized neuropathic event in the liver with metabolic relevance.