Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism.
Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism.
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肥胖症中肝ER应力的细胞间传播破坏了系统性代谢。
DOI：
10.1016/j.cmet.2020.11.009
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发表时间：
2021-02-02
期刊：
影响因子：
29
通讯作者：
Hotamisligil GS
中科院分区：
文献类型：
--
作者：
Tirosh A;Tuncman G;Calay ES;Rathaus M;Ron I;Tirosh A;Yalcin A;Lee YG;Livne R;Ron S;Minsky N;Arruda AP;Hotamisligil GS
内质网应激（ERS）在肥胖相关的胰岛素抵抗中具有病理生理作用。然而，组织对ERS的协调反应仍不清楚。连接蛋白（Cx）43介导的细胞间通讯的增加，已被牵连在组织适应性和适应不良的各种慢性应激反应。在这里，我们证明，在肝细胞中，ERS的结果增加Cx43的表达和细胞-细胞耦合。ER应激的“供体”细胞的共培养导致ERS的细胞间传递和对ERS-幼稚的“受体”细胞的功能障碍（“旁观者反应”），这可以通过Cx43的遗传或药理学抑制来预防。来自肥胖小鼠的肝细胞能够将ERS传递给来自瘦小鼠的肝细胞，缺乏肝脏Cx43的小鼠免受饮食诱导的ERS、胰岛素抵抗和脂肪肝的影响。两者合计，我们的研究结果表明，在肥胖症，增加Cx43介导的细胞-细胞耦合允许ERS的细胞间传播。这种对营养过剩的新型适应不良反应加剧了组织ERS负担，促进脂肪肝并损害全身葡萄糖代谢。连接蛋白43（Cx43）在细胞间通讯中起着重要作用。虽然Cx43介导的细胞间通讯是急性应激中的适应性组织反应，但它在慢性非缓解应激条件下可能变得有害。在此，Tirosh等人发现，在肥胖症中，Cx43允许有害信号在肝脏细胞之间传播，导致脂肪肝疾病和代谢改变。
Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin (Cx)43-mediated intercellular communication, has been implicated in tissue adaptive and maladaptive response to various chronic stresses. Here we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER stressed ‘donor’ cells resulted in inter-cellular transmission of ERS and dysfunction to ERS-naïve ‘recipient’ cells (‘bystander response’), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows inter-cellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism. Connexin-43 (Cx43) has a key role in cell-cell communication. While Cx43-mediated inter-cellular communication is an adaptive tissue response in acute stress, it may become deleterious under chronic, non-resolving stress conditions. Herein, Tirosh et al. discover that in obesity, Cx43 allows deleterious signals to disseminate between cells in the liver, leading to fatty-liver disease and metabolic alterations.
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影响因子：
8.8
作者：
Charles KN;Li MD;Engin F;Arruda AP;Inouye K;Hotamisligil GS
通讯作者：
Hotamisligil GS
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
间隙连接和半通道：神经发育和疾病中的细胞死亡。
影响因子：
--
作者：
Belousov AB;Fontes JD;Freitas-Andrade M;Naus CC
通讯作者：
Naus CC
影响因子：
3.3
作者：
Gunawardena J
通讯作者：
Gunawardena J
影响因子：
82.9
作者：
Iwawaki, T;Akai, R;Miura, M
通讯作者：
Miura, M