近日，《Cell Metabolism》在線發(fā)表了哈佛大學(xué)公共衛(wèi)生學(xué)院Gkhan S. Hotamisligil團(tuán)隊(duì)名為“Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism”的研究。該研究表明，營養(yǎng)過剩會(huì)加劇組織的內(nèi)質(zhì)網(wǎng)應(yīng)激，并通過細(xì)胞通訊傳遞到臨近細(xì)胞，促進(jìn)肝脂肪變性、損害了全身葡萄糖代謝。

Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-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 intercellular transmission of ERS and dysfunction to ERS-naive “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 intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism.

在多細(xì)胞生物中，形態(tài)和功能的多樣性是動(dòng)物進(jìn)化的關(guān)鍵，其中細(xì)胞通訊是細(xì)胞間進(jìn)行相互作用的有效途徑?？p隙連接(GJ)是最常見的細(xì)胞間通訊形式之一，GJ蛋白在多種生理過程中發(fā)揮著關(guān)鍵作用，如分化和增殖、神經(jīng)元信號(hào)、激素分泌和免疫反應(yīng)。在21個(gè)人類Cx（connexin）基因中，連接蛋白43(Cx43)是一個(gè)43 kDa的蛋白，是最普遍和最關(guān)鍵的GJ蛋白，在許多組織中發(fā)揮著重要的發(fā)育、調(diào)節(jié)和病理生理作用。

當(dāng)肥胖和2型糖尿病困擾人們時(shí)，機(jī)體會(huì)處于低水平的代謝性炎癥和細(xì)胞應(yīng)激狀態(tài)。特別是，肝臟內(nèi)質(zhì)網(wǎng)應(yīng)激（ERS）和功能障礙在調(diào)控胰島素抵抗和糖尿病發(fā)展的應(yīng)激信號(hào)網(wǎng)絡(luò)中起著關(guān)鍵作用，從而破壞系統(tǒng)血糖穩(wěn)態(tài)。目前細(xì)胞通訊在組織和器官水平上協(xié)調(diào)反應(yīng)的潛在作用尚不清楚。

首先，研究人員評(píng)估了ERS對(duì)肝細(xì)胞系和分離的原代小鼠肝細(xì)胞中Cx43表達(dá)的直接影響，發(fā)現(xiàn)化學(xué)誘導(dǎo)ER應(yīng)激可使Cx43水平升高。并且，內(nèi)質(zhì)網(wǎng)應(yīng)激可增加GJ介導(dǎo)的細(xì)胞-細(xì)胞通訊

肝細(xì)胞中肥胖可增加Cx43的表達(dá)

隨后，研究人員將C57BL/6小鼠暴露于高脂飲食(HFD)16周，發(fā)現(xiàn)HFD飲食導(dǎo)致肝臟ER增加，Cx43的表達(dá)升高。值得注意的是，肝臟中Cx43表達(dá)的增加發(fā)生在過度營養(yǎng)的早期，僅在服用HFD 3天后觀察到。

Cx43介導(dǎo)細(xì)胞間通訊

除此之外研究人員還發(fā)現(xiàn)，Cx43介導(dǎo)的ER細(xì)胞間傳遞可引起受體細(xì)胞分子伴侶的活性和內(nèi)質(zhì)網(wǎng)折疊能力降低，以及胰島素抵抗。肝臟中Cx43缺失，可降低肝細(xì)胞-肝細(xì)胞間通訊，阻止內(nèi)質(zhì)網(wǎng)應(yīng)激在細(xì)胞間傳遞，對(duì)飲食誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激、肝骨病和全身代謝改變具有保護(hù)作用

肥胖時(shí)Cx43介導(dǎo)有害的細(xì)胞間通訊，導(dǎo)致脂肪肝和新陳代謝改變

總而言之，研究人員首次發(fā)現(xiàn)在飲食誘導(dǎo)的肥胖早期Cx43就表達(dá)上調(diào)，導(dǎo)致Cx43介導(dǎo)的細(xì)胞間通訊增加，從而使得內(nèi)質(zhì)網(wǎng)應(yīng)激信號(hào)傳遞到鄰近細(xì)胞，導(dǎo)致內(nèi)質(zhì)網(wǎng)功能受損和胰島素抵抗。通過調(diào)控Cx43的水平可改善全身的葡萄糖代謝，起到有效的保護(hù)作用。

研究用相關(guān)儀器設(shè)備： 離心機(jī)、PCR、電泳、顯微鏡等