新一期的《糖尿病學(xué)術(shù)前沿》又和大家見(jiàn)面了。本期學(xué)術(shù)前沿相關(guān)內容如下：
關(guān)注雙酚A（BPA）等內分泌干擾物：介導免疫調節代謝機制探討
雙酚A（BPA）等內分泌干擾物可能通過(guò)介導免疫系統來(lái)影響代謝健康，本期將分享相關(guān)內容。
研究表明，內分泌干擾物（EDCs）可能通過(guò)介導免疫系統來(lái)影響代謝健康，該領(lǐng)域的研究可能為未來(lái)代謝性疾病的預防和治療提供新的思路。本期將分享相關(guān)內容。
一、什么是內分泌干擾物（EDCs）？
代謝紊亂疾病如2型糖尿病和肥胖癥的發(fā)病率逐年增加1, 2。造成這一現象的原因是多方面的。除卻已知的營(yíng)養過(guò)剩和不良生活方式這兩個(gè)主要因素，暴露于環(huán)境中的各種化學(xué)物質(zhì)可能也是一個(gè)重要原因3-7。由于這些外源性化學(xué)物質(zhì)可從多個(gè)方面破壞內分泌激素的正常作用，因此也被稱(chēng)為內分泌干擾物（EDCs）8,9。
EDCs種類(lèi)多且復雜,按其來(lái)源可分為天然和人工合成化合物兩大類(lèi)。它們會(huì )增加糖尿病和肥胖的風(fēng)險，尤以雙酚A（BPA）10和鄰苯二甲酸酯11這兩種物質(zhì)為甚。
研究表明，ECDs可能通過(guò)介導免疫系統來(lái)影響代謝健康12,13。更好地理解EDCs的免疫調節作用，將有助于改善代謝功能，并有助于減輕由生活環(huán)境所致的糖尿病和肥胖的負擔。
二、免疫系統如何調節代謝健康？
代謝健康的免疫調節近年來(lái)受到了廣泛關(guān)注。固有免疫系統（自然殺傷細胞、肥大細胞、嗜酸性粒細胞、嗜堿性粒細胞和巨噬細胞的吞噬細胞，如樹(shù)突狀細胞和中性粒細胞）和適應性免疫應答系統（CD8+和CD4+ T淋巴細胞，以及B淋巴細胞）都在代謝疾病進(jìn)展中發(fā)揮關(guān)鍵影響。
在脂肪組織中，這兩套免疫系統之間的交互作用已被廣泛探討14。 肥胖時(shí)肥大的脂肪細胞產(chǎn)生趨化性脂肪細胞因子和趨化因子，如單核細胞趨化蛋白-1（MCP-1）和白三烯B4 （LTB4）。此外，脂肪組織會(huì )釋放促炎性細胞因子，如腫瘤壞死因子α（TNF-α）、γ-干擾素（IFN-γ）和白細胞介素17（IL-17），促進(jìn)脂肪組織巨噬細胞向促炎性M1巨噬細胞轉化15。脂肪細胞、固有免疫系統和適應性免疫系統的交互作用造就了脂肪組織的促炎癥環(huán)境。
與之類(lèi)似，在胰島素抵抗和2型糖尿病中，代謝敏感組織（胰腺、肝臟、骨骼肌、腸和血管）中固有免疫和適應性免疫的交互作用，打破了促炎和抗炎的平衡，最終干擾了代謝健康16。
與代謝紊亂相關(guān)的細胞內促炎信號通路共有三條，分別是核因子kB/kB激酶抑制劑通路（NFκB)/ IKκB）、c-Jun氨基末端激酶/激活蛋白-1通路（JNK/AP1），以及炎性小體通路17, 18（圖2）。這三條通路經(jīng)常交疊作用。促炎信號通路一旦激活，則會(huì )增加胰島素受體底物1/2（IRS1 / 2）磷酸化以及炎癥基因的轉錄，從而增加胰島素抵抗17, 18（圖1）。
與促炎信號通路相反，由G蛋白偶聯(lián)受體120（GPR120）、雌激素受體α（ERα）和白介素10（IL-10）激活的抗炎信號通路則可抑制胰島素抵抗17-19 (圖1)。促炎和抗炎因子水平的平衡決定著(zhù)炎癥的大小量級，并對維持代謝平衡起著(zhù)至關(guān)重要的作用。
圖1. 胰島素抵抗的炎癥相關(guān)信號通路
三、EDCs對免疫系統的影響機制
EDCs對免疫系統的影響機制可能是多方面的。其中已發(fā)現對維持代謝平衡有重要作用的機制有以下四種（圖2）。
1. 受體。EDCs通過(guò)與受體結合來(lái)影響免疫系統，如雌激素受體（ERS）、雌激素相關(guān)受體（ERR）、過(guò)氧化物酶體增殖物激活受體γ（PPARγ）、Toll樣受體（TLR）和NOD樣受體（NLRs）20-23。
2. 腸道菌群。腸道菌群的個(gè)體差異很大，不同的腸道菌群會(huì )帶來(lái)不同的EDCs代謝24。綜合以往的研究，EDC會(huì )損傷正常的腸道菌群并對代謝健康帶來(lái)不利的影響25-27。
3. 氧化應激。體內體外研究都顯示EDCs可以增加腎臟、胰腺和肝臟的內質(zhì)網(wǎng)應激28-31。線(xiàn)粒體功能障礙和內質(zhì)網(wǎng)應激與氧化應激增強和代謝紊亂相關(guān)。
4. 晝夜節律破壞。晝夜節律紊亂會(huì )損害體內的代謝平衡，同樣，生活方式的因素，如睡眠/喚醒模式、輪班工作、時(shí)差等導致的晝夜節律紊亂，均會(huì )改變免疫系統功能。最近的研究表明，EDCs可以擾亂晝夜節律性32-34。
圖2. EDC作用于免疫系統從而導致代謝紊亂的可能路徑
免疫功能障礙增加了糖尿病和肥胖等各種代謝紊亂的風(fēng)險，而無(wú)處不在的EDCs又使風(fēng)險進(jìn)一步加劇。在未來(lái)針對EDC領(lǐng)域的研究中，應把EDC對免疫系統的作用考慮在內，從而找到新的針對環(huán)境引起的代謝疾病的預防和治療方法。
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