【原】生物鐘基因與非酒精性脂肪性肝病

臨床肝膽病雜志 2019-12-13

展開全文

非酒精性脂肪性肝病 (NAFLD) 指除外酒精和其他明確損肝因素所致的, 以肝細(xì)胞脂肪變性和脂質(zhì)沉積為特征的臨床病理綜合征,。其組織學(xué)亞型——非酒精性脂肪性肝炎作為重要的肝纖維化前期病變,，如未行積極診治，可逐漸進(jìn)展為肝硬化,，甚至肝癌等終末期肝病,。NAFLD已經(jīng)成為最普遍的慢性肝病之一。流行病學(xué)研究發(fā)現(xiàn)全球NAFLD患病率為2524%,，亞洲人NAFLD患病率為27.37%,，且亞洲NAFLD患者肥胖癥的患病率為67%。目前我國(guó)NAFLD患病率呈明顯上升趨勢(shì),，因此明確其發(fā)病機(jī)制并積極進(jìn)行防治十分重要,。

1 生物鐘概述

1.1 生物鐘的形成

生物鐘是生物體為適應(yīng)外在環(huán)境而在長(zhǎng)期的進(jìn)化過程中形成的內(nèi)在節(jié)律。地球自轉(zhuǎn)使得晝夜交替,，生物體為了適應(yīng)光照,、溫度等變化而出現(xiàn)一系列的生理和行為變化。哺乳動(dòng)物體內(nèi)的生物鐘分別由中樞生物鐘（下丘腦視交叉上核,，SCN）和外周生物鐘(肝,、腸、腎,、心和脾）組成,，SCN起著主要的調(diào)控作用，也稱為核心鐘,，它們共同調(diào)控生物體的各種生理和行為活動(dòng)。SCN通過直接接收來自視網(wǎng)膜的光輸入來感知一天中的時(shí)間,，使得中樞生物鐘相位與光相位同步,，晝夜節(jié)律周期達(dá)到24 h。通過神經(jīng)和體液信號(hào),，SCN將此信息發(fā)送到大腦其他區(qū)域和外周生物鐘,，這些生物鐘幾乎存在于身體其他部分的所有細(xì)胞中，并將它們同步到同一階段,。中樞生物鐘節(jié)律僅對(duì)光照/黑暗變化發(fā)生反應(yīng),，而外周生物鐘節(jié)律不但可受中樞生物鐘的調(diào)控，其自身還能根據(jù)某些外部環(huán)境影響（如溫度,、飲食控制和進(jìn)食時(shí)間）達(dá)到自我調(diào)控,，從而達(dá)到機(jī)體自我保護(hù)的穩(wěn)態(tài)平衡。

1.2 生物鐘的分子調(diào)控機(jī)制

生物鐘在分子水平上由多個(gè)生物鐘基因精確調(diào)控,，如circadian locomotor output cycles kaput(CLOCK),、brain and muscle arylhydrocarbo receptor nuclear translocator(ARNT)-like protein-1(BMAL1),、period(Per, Per1、Per2,、Per3),、cryptochrome(Cry, Cry1、Cry2）,、neuronal Per-Arnt-Sim domain protein 2(NPAS2),、nuclear receptor subfamily 1 group D member 1(NR1D1,也稱Rev-Erbα)、peroxisome proliferator-activated receptor alpha(PPARα)等,。

生物鐘基因CLOCK通過bHLH-PAS結(jié)構(gòu)域與BMAL1形成異源二聚體,，同Per和Cry基因啟動(dòng)子上的E盒相結(jié)合并激活其轉(zhuǎn)錄，表達(dá)產(chǎn)物Per和Cry系列蛋白由細(xì)胞胞漿轉(zhuǎn)移至胞核內(nèi),，作為負(fù)性元件與CLOCK/BMAL1直接結(jié)合并抑制其活性,，進(jìn)而阻遏Per和Cry的進(jìn)一步轉(zhuǎn)錄；CLOCK與BMAL1形成的異二聚體除了激活Per和Cry基因轉(zhuǎn)錄外,，也激活了孤兒核受體Rev-Erb基因的轉(zhuǎn)錄,。Rev-Erb基因編碼蛋白可與BMAL1啟動(dòng)子相結(jié)合并阻遏其轉(zhuǎn)錄。生物鐘基因這種負(fù)反饋循環(huán)結(jié)構(gòu)形成人體內(nèi)精確的內(nèi)源性“分子鐘”,，并通過其下游的鐘控基因?qū)⑸镧姷墓?jié)律信號(hào)輸出,，從而使細(xì)胞內(nèi)的分子活動(dòng)也呈現(xiàn)出時(shí)間節(jié)律。

2 NAFLD發(fā)病機(jī)制

目前NAFLD的發(fā)病機(jī)制尚未明確,，但已經(jīng)完成從 “二次打擊學(xué)說”到“多重打擊模型”的演變,。“多重打擊模型”認(rèn)為第一次打擊仍是由胰島素抵抗（IR）引發(fā)肝臟脂質(zhì)沉積,，但第二次打擊僅由氧化應(yīng)激及脂質(zhì)過氧化損傷概括似乎難以解釋NAFLD的復(fù)雜性,。脂代謝紊亂引起肝臟脂質(zhì)沉積是NAFLD 的重要病因，IR使胰島素抑制脂肪分解作用減弱,，引起血漿游離脂肪酸（FFA）濃度升高,，被肝細(xì)胞攝取后甘油三酯合成增多，促使脂質(zhì)沉積,。肝臟積累的脂質(zhì)分子又通過干擾細(xì)胞胰島素受體底物的酪氨酸磷酸化和信號(hào)轉(zhuǎn)導(dǎo)加重IR,。IR與脂代謝紊亂相互影響，共同推動(dòng)NAFLD病程進(jìn)展,。在IR與FFA增多的基礎(chǔ)上,，微粒體內(nèi)的脂質(zhì)過氧化物酶上調(diào)，線粒體內(nèi)的β氧化作用增強(qiáng),，導(dǎo)致肝臟對(duì)氧化應(yīng)激更加敏感,，從而增加了肝臟受損的程度。線粒體活性氧反應(yīng)產(chǎn)物的改變會(huì)促進(jìn)體內(nèi)氧化還原反應(yīng)的一系列變化,而這些變化會(huì)改變氨基末端激酶的活性，并且擾亂胰島素信號(hào),。

此外,，F(xiàn)FA水平上升可導(dǎo)致脂毒性和IR，并與其他因素（如腸源性內(nèi)毒素）一起促進(jìn)炎癥因子IL-6,、TNFα,、IL-4等的釋放，肝臟長(zhǎng)期暴露于高水平炎癥因子可導(dǎo)致與非酒精性脂肪性肝炎相似的組織學(xué)變化,，并且IL-6,、TNFα等能夠使脂聯(lián)素水平降低和瘦素水平升高，脂聯(lián)素具有抗炎,、抗動(dòng)脈粥樣硬化及抗糖尿病的特性,，瘦素水平增高可導(dǎo)致慢性炎癥在肥胖患者中的循環(huán)永久化。菌群失調(diào)或腸道屏障破壞會(huì)增加細(xì)菌流入肝臟,，從而通過激活Toll樣受體和其他模式識(shí)別受體來促進(jìn)炎癥反應(yīng),。此外，NAFLD發(fā)病還與飲食因素及遺傳因素相關(guān),。這些因素相互影響,、共同作用，導(dǎo)致NAFLD的發(fā)生,。

3 生物鐘基因表達(dá)對(duì)脂代謝的影響

研究發(fā)現(xiàn)Per2基因敲除小鼠空腹血糖降低,，肝糖原積累減少，血漿胰島素水平升高,糖異生受損,，并且血脂水平降低,，在高脂飲食下體質(zhì)量增加較野生型更為明顯。這說明生物鐘基因Per2不僅在調(diào)節(jié)基因表達(dá)中起作用,，對(duì)新陳代謝也有重要影響,。此外，Per2可以特異性地抑制PPARγ,，PPARγ是氧化應(yīng)激,、炎癥反應(yīng)、葡萄糖及脂質(zhì)代謝的關(guān)鍵核受體,，缺乏PER2基因會(huì)影響脂質(zhì)代謝，其特征在于血漿甘油三酯和FFA的快速減少,。生物鐘基因Per2在脂肪肝肝組織中的表達(dá)明顯低于正常肝組織,，NAFLD患者肝細(xì)胞PPARγ和aP2高表達(dá)，肝組織中增多的FFA和類花生酸與PPARγ相互作用,，可激活生物鐘基因上游的調(diào)節(jié)元件從而調(diào)節(jié)BMAL1的活性,。PPARα激活肝臟中的BMAL1和Rev-Erbα, PPAR的配體包括各種類型的脂質(zhì)，其中在小腸中產(chǎn)生和釋放的腸道循環(huán)代謝產(chǎn)物油酰乙醇胺，在PPARα依賴下,休息期間可抑制食物攝入,。Rev-Erbα是一種調(diào)節(jié)脂質(zhì)代謝和脂肪生成的核受體,，受生物鐘調(diào)節(jié)并抑制BMAL1表達(dá)。Rev-Erbα和Rev-Erbβ雙敲的小鼠會(huì)出現(xiàn)血糖和甘油三酯水平升高,，但是FFA水平降低,，F(xiàn)FA降低可反映氧化代謝的增加。Rev-Erbs基因可通過調(diào)控INSIG2-SREBP信號(hào)通路參與脂質(zhì)代謝,。

多項(xiàng)研究發(fā)現(xiàn)Cry1或Cry2基因敲除小鼠葡萄糖不耐受,，皮質(zhì)酮水平升高，肝臟中糖皮質(zhì)激素（GC）反式激活增加,，脂肪生成和類固醇生成途徑改變,，以及身體生長(zhǎng)和肝臟再生受損。Cry1可通過阻斷胰高血糖素的腺苷酸環(huán)化酶信號(hào)傳導(dǎo)來抑制肝臟糖異生,，Cry1和Cry2雙敲除動(dòng)物的糖異生增加,。

CLOCK或BMAL1敲除小鼠會(huì)出現(xiàn)葡萄糖耐量降低，胰島素分泌減少,，胰島增殖缺陷,，且癥狀隨著年齡的增長(zhǎng)而加重。肝臟特異性敲除BMAL1可導(dǎo)致肝臟的關(guān)鍵代謝基因振蕩喪失,，引起糖異生受損,、葡萄糖過度清除和靜息期間的低血糖，并加重肝細(xì)胞氧化損傷,、誘發(fā)IR,；胰腺特異性BMAL1敲除則導(dǎo)致高血糖、葡萄糖耐量降低及由于β細(xì)胞增殖和胰島素顆粒胞吐作用導(dǎo)致的胰島素減少,，因此,，組織特異性生物鐘在胰島和肝臟中具有不同的作用，影響相反的代謝過程,，從而在喂食和禁食期間促進(jìn)葡萄糖穩(wěn)定性,。恢復(fù)高脂飲食小鼠的BMAL1活性能逆轉(zhuǎn)線粒體的腫脹形態(tài)并改善線粒體功能,。由上述研究可知生物鐘基因與脂質(zhì)代謝密切相關(guān),。

4 生物鐘基因調(diào)控影響GC水平

作為全身晝夜節(jié)律的夾帶信號(hào)，GC節(jié)律在協(xié)調(diào)糖,、脂質(zhì)和蛋白質(zhì)代謝中起關(guān)鍵作用,。在無壓力條件下，循環(huán)中的GC水平顯示出在活躍期開始時(shí)的強(qiáng)烈日常節(jié)律性峰值（即人類的早晨和夜間嚙齒動(dòng)物的夜晚）,。GC晝夜節(jié)律由中樞和外周生物鐘協(xié)調(diào),。SCN控制下丘腦-垂體-腎上腺軸的晝夜節(jié)律功能,，以誘導(dǎo)GC的節(jié)律性產(chǎn)生和分泌。肝臟,、脂肪組織和腎臟中的外周時(shí)鐘由SCN通過自主神經(jīng)系統(tǒng)和有節(jié)奏的夾帶信號(hào)（例如GC）調(diào)節(jié),。

研究發(fā)現(xiàn)GC和進(jìn)食模式的晝夜節(jié)律在Per2基因敲除小鼠中變得紊亂。Cry1和Cry2可以以配體依賴性方式與糖皮質(zhì)激素受體（GR）的C末端結(jié)構(gòu)域相互作用,，抑制GR介導(dǎo)的某些靶基因的反式激活,。Cry1和Cry2的缺失導(dǎo)致GR介導(dǎo)的GC合成受損。缺乏Cry1或Cry2的小鼠在注射葡萄糖后恢復(fù)正常血糖的能力也顯著受損,。CLOCK/BMAL1異二聚體與GR相互作用,，從而降低其對(duì)GC反應(yīng)元件的親和力及其向細(xì)胞核的易位。此外,，Rev-Erbα可以通過與熱休克蛋白90的相互作用來穩(wěn)定GR的核定位,，從而增強(qiáng)其轉(zhuǎn)錄活性。通過這種復(fù)雜的相互作用網(wǎng)絡(luò),，GR最終在生理反應(yīng)中轉(zhuǎn)化環(huán)境信息,。

5 生物鐘基因與氧化應(yīng)激變化

環(huán)磷酸腺苷不僅僅是SCN的輸出，還是SCN起搏器的一個(gè)組成部分,，調(diào)節(jié)轉(zhuǎn)錄周期,。細(xì)胞能量狀態(tài)也影響氧化還原狀態(tài)，食物攝入通過該途徑可能影響晝夜節(jié)律,。實(shí)際上,，體外實(shí)驗(yàn)已經(jīng)表明，煙酰胺腺嘌呤二核苦酸的氧化還原狀態(tài)可以調(diào)節(jié)CLOCK/BMAL1異二聚體的DNA結(jié)合活性,，這表明細(xì)胞氧化還原變化可能足以改變生物鐘,。體內(nèi)NAD水平受到晝夜節(jié)律的影響，從而為生物鐘提供有節(jié)奏的輸入,但也有一些間接途徑,，氧化還原狀態(tài)可通過這些途徑與時(shí)鐘相關(guān)聯(lián),。最近的研究進(jìn)一步確定了細(xì)胞氧化還原狀態(tài)的24 h節(jié)律，其控制過氧化物酶抗氧化酶家族氧化態(tài)的晝夜節(jié)律振蕩,。有研究發(fā)現(xiàn)參與脂質(zhì)和葡萄糖代謝的線粒體限速酶依賴Per1和Per2蛋白的調(diào)控,，Per1/2缺乏或高脂飲食的小鼠會(huì)出現(xiàn)線粒體呼吸調(diào)節(jié)遲鈍。這些研究提出了細(xì)胞氧化還原狀態(tài)的振蕩可能控制代謝過程的晝夜節(jié)律并且可能獨(dú)立于生物鐘轉(zhuǎn)錄反饋環(huán),。

6 展望

綜上,，目前許多研究已證實(shí)生物鐘基因紊亂可導(dǎo)致與NAFLD發(fā)病密切相關(guān)的脂代謝異常、氧化應(yīng)激,、IR,、GC分泌異常等，但生物鐘基因紊亂是否能成為NAFLD發(fā)生發(fā)展過程中的又一打擊因素,，其機(jī)制仍有待繼續(xù)探索。

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