研究揭示肥胖形成中的「連鎖反應」
作者：
小柯機器人發布時間：2020/12/22 12:55:31
美國哈佛大學Gkhan S. Hotamisligil、Amir Tirosh等研究人員合作發現，肥胖中肝臟內質網應激的細胞間傳遞可破壞系統性代謝。該研究於2020年12月18日在線發表於國際一流學術期刊《細胞—代謝》。
研究人員證明，在肝細胞中，內質網應激（ERS）導致連接蛋白43（Cx43）表達增加和細胞間偶聯。內質網應激「供體」細胞的共培養導致ERS的細胞間傳播以及對ERS-naive「受體」細胞的功能障礙（「旁觀者反應」），這可以通過Cx43的遺傳或藥理抑制來預防。肥胖小鼠的肝細胞能夠將ERS傳遞給瘦小鼠的肝細胞，缺乏肝臟Cx43的小鼠受到飲食誘導的ERS、胰島素抵抗和肝脂肪變性的保護。
總之，這些結果表明，在肥胖症中，Cx43增加介導的細胞間偶聯促使ERS的細胞間傳播。這種對營養過剩的新型適應不良反應加劇了組織的ERS負擔，促進了肝脂肪變性並損害了全身性葡萄糖代謝。
據介紹，ERS在肥胖相關的胰島素抵抗中具有病理生理作用。然而，對ERS的組織協調反應仍不清楚。Cx43介導的細胞間交流增加與組織對各種慢性應激的適應性反應有關。
附：英文原文
Title: Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism
Author: Amir Tirosh, Gurol Tuncman, Ediz S. Calay, Moran Rathaus, Idit Ron, Amit Tirosh, Abdullah Yalcin, Yankun G. Lee, Rinat Livne, Sophie Ron, Neri Minsky, Ana Paula Arruda, Gkhan S. Hotamisligil
Issue&Volume: 2020-12-18
Abstract: Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associatedinsulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increasedconnexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptiveand -maladaptive response to various chronic stresses. Here, we demonstrate that inhepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-cultureof ER-stressed 「donor」 cells resulted in intercellular transmission of ERS and dysfunctionto ERS-naive 「recipient」 cells (「bystander response」), which could be prevented bygenetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were ableto transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protectedfrom diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, ourresults indicate that in obesity, the increased Cx43-mediated cell-cell coupling allowsintercellular propagation of ERS. This novel maladaptive response to over-nutritionexacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-bodyglucose metabolism.
DOI: 10.1016/j.cmet.2020.11.009
Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30604-5