膽固醇調(diào)節(jié)元件結(jié)合蛋白(SREBPs)，是一類能與膽固醇調(diào)節(jié)元件1(SRE-1)發(fā)生特異性結(jié)合的“堿性螺旋-環(huán)-螺旋-亮氨酸拉鏈”(bHLH-ZZP)蛋白。在細(xì)胞內(nèi)缺乏膽固醇的情況下，SREBPs通過和SRE-1的結(jié)合，激活SRE-1的基因，使其翻譯增強(qiáng)，發(fā)揮生理功能。
一、膽固醇調(diào)節(jié)元件1的功能和定位
編碼低密度脂蛋白受體(LDL-R)的基因5'側(cè)翼區(qū)，具有一個(gè)長10個(gè)堿基對(duì)的膽固醇調(diào)節(jié)元件1(sterol regulatory element 1,SRE-1)。SRE-1是一個(gè)條件正性調(diào)節(jié)元件，僅在細(xì)胞內(nèi)膽固醇缺乏的條件下，才被激活。在其他的膽固醇調(diào)節(jié)基因如羥甲基戊二酸單酰CoA合酶(HMGCoa synthase )基因的啟動(dòng)子中也含有SRE-1，而在羥甲基戊二酸單酰CoA還原酶(HMGCoa reductase )基因的啟動(dòng)子中含有類似于SRE-1的膽固醇調(diào)節(jié)元件(SRE)。SRE-1通過調(diào)節(jié)LDL-R基因、HMGCoA合酶基因的翻譯，控制細(xì)胞對(duì)外源性膽固醇的攝取量和內(nèi)源性膽固醇的合成速率，調(diào)節(jié)細(xì)胞內(nèi)膽固醇含量。SRE-1在LDL-R基因5'側(cè)翼區(qū)的定位見圖7-9。
圖7-9 +1表示翻譯起始位點(diǎn)，T/A表示TATA盒，空心箭頭表示重復(fù)區(qū)，重復(fù)區(qū)1、重復(fù)區(qū)3可能和Sp1(一種正性翻譯因子)結(jié)合。重復(fù)區(qū)2內(nèi)含有SRE-1。
二、SREBPs的發(fā)現(xiàn)和命名
1989年，Tripathi B.Rajavashisth發(fā)現(xiàn)了一種能和SRE結(jié)合的鋅脂蛋白。1993年，Michael R.Briggs等人，利用離子交換層析、凝膠過濾和DNA親和層析的方法，從人類宮頸癌細(xì)胞(Hela細(xì)胞)核的提取物中分離出了這一組能與SRE-1結(jié)合的蛋白質(zhì)，并將其命名為膽固醇調(diào)節(jié)元件結(jié)合蛋白(sterol regulatory element-binding proteins, SREBPs)。SREBPs在細(xì)胞膽固醇缺乏的情況下，通過和SRE-1的結(jié)合，激活LDLR基因、HMGCoA合酶基因的翻譯。
三、SREBPs的結(jié)構(gòu)和分類
SREBPs具有“堿性螺旋-環(huán)-螺旋-亮氨酸拉鏈”(basic helix-loop-helix-leucine zipper, bHLH-ZIP)結(jié)構(gòu)，是bHLH-ZIP蛋白系列的一種。bHLH-ZIP蛋白包含一系列能特異性地和含E盒(e box, CANNTG)的DNA結(jié)合的蛋白質(zhì)，例如：調(diào)節(jié)免疫球蛋白基因翻譯的TFE3，致腫瘤蛋白Myc等。SREBPs雖是bHLH-ZIP蛋白中的一種，但又不同于其他的bHLH-ZIP蛋白。一方面，SREBPs分子量大，含1140個(gè)左右的氨基酸殘基；另一方面，SREBPs不識(shí)別E盒(e box)而特定地識(shí)別SRE-1中直接重復(fù)的“CAC”序列。
迄今為止，發(fā)現(xiàn)有兩種SREBPs。一種稱SREBP-1，另一種稱SREBP-2。SREBP-1又由于其mRNA剪接方式的不同，以三種功能上完全相同，組成上略有不同的形式大量存在，這三種形式的蛋白分別稱為SREBP-1a、SREBP-1b、SREBP-1c。其中，SREBP-1a是SREBP-1的主要存在形式，故本文以SREBP-1a為例來描述SREBP-1。SREBP-1a含1147個(gè)氨基酸殘基。分子量為125kD。至今，還沒有發(fā)現(xiàn)SREBP-2存在多種不同的剪接后蛋白。SREBP-2含1141個(gè)氨基酸殘基，分子量為121kD，與SREBP-1a之間有47%的同源性，含高度保守的bHLH-ZIP區(qū)，和SREBP-1a的bHLH-ZIP區(qū)有71%的一致性。但是SREBP-2含有不同SREBP-1a的谷氨酸富集區(qū)(在121個(gè)氨基酸殘基中含多于27%的谷氨酸殘基。SREBP-1a和SREBP-2的氨基酸序列和功能域結(jié)構(gòu)之間的比較參見圖7-10(A、B、C)。
圖7-10 A：SREBP-2和SREBP-1a氨基酸序列之間的比較
“--”表示二者的相同部分
圖7-10 B：SREBP-2和SREBP-1a的bHLH區(qū)(粗橫線所示)的比較
四、SREBPs的生理功能
兩種SREBPs利用位于其氨基酸殘基470～570之間的疏水序列，附著于內(nèi)質(zhì)網(wǎng)膜和核膜，在氨基端的470個(gè)氨基酸殘基組成的肽鏈中，均含“堿性螺旋-環(huán)-螺旋-亮氨酸拉鏈”的核心結(jié)構(gòu)，使蛋白質(zhì)能形成均一二聚體，并能和SRE-1結(jié)合。兩種蛋白質(zhì)氨基端一側(cè)的結(jié)構(gòu)中，都有酸性區(qū)域，可能作為DNA翻譯的增強(qiáng)子。當(dāng)人或倉鼠細(xì)胞在缺乏膽固醇的環(huán)境中培養(yǎng)時(shí)，蛋白酶在亮氨酸拉鏈和膜間的附著區(qū)處裂解SREBPs，并從膜上釋放出水溶性的氨基端的裂解片段，這一片段約含470個(gè)氨基酸殘基，表現(xiàn)分子量為68kD。這一片段能夠移行入胞核，結(jié)合于SRE-1，從而激活LDLR基因翻譯和HMGCoA合酶基因翻譯。
SREBPs裂解、移行入胞核，進(jìn)而結(jié)合于SRE-1，以致激活LDLR基因、HMGCoA合酶基因，都有賴于細(xì)胞內(nèi)缺乏膽固醇。因?yàn)槟懝檀寄軌蛞种芐REBPs的裂解。而已形成的SREBPs的裂解片段又很容易被迅速分解，從細(xì)胞核中快速消失。故而膽固醇的存在，將阻斷整個(gè)調(diào)節(jié)通路，使SRE-1失活。
將SREBP-1和SREBP-2進(jìn)行cDNAg隆，并采用質(zhì)粒轉(zhuǎn)染動(dòng)物細(xì)胞的方法，使培養(yǎng)細(xì)胞，如Hela細(xì)胞和中國倉鼠卵巢細(xì)胞(CHO細(xì)胞)，表達(dá)SREBP-1和SREBP-2，發(fā)現(xiàn)他們調(diào)節(jié)細(xì)胞內(nèi)膽固醇代謝的過程是一致的，功能上是協(xié)同的，然而兩種蛋白質(zhì)是單獨(dú)發(fā)生作用，沒有發(fā)現(xiàn)雜化二聚體。為什么存在這兩種組成不同但功能一致的SREBPs，原因還不清楚。
研究倉鼠肝臟中產(chǎn)生的，由細(xì)胞內(nèi)膽固醇含量調(diào)節(jié)的mRNA(包括LDLR和HMGCoA合酶的mRNA)的含量。肝臟經(jīng)HMGCoA還原酶抑制物mevinolin處理后，這兩種mRNA的量都增加。通過阻止膽固醇的合成，mevinolin誘導(dǎo)暫時(shí)的膽固醇水平降低，而增強(qiáng)膽固醇調(diào)節(jié)基因的翻譯。當(dāng)mevinolin和膽汁酸結(jié)合樹酯，如降膽靈合用時(shí)，mevinolin增強(qiáng)翻譯的效果更強(qiáng)。降膽寧通過阻止腸道對(duì)膽汁酸的再吸收，使膽固醇轉(zhuǎn)變?yōu)槟懼幔蚨黾痈闻K對(duì)膽固醇的進(jìn)一步需求。
最近，研究HMGCoA還原酶抑制物和膽汁酸結(jié)合樹酯是否促進(jìn)SREBP-1和SREBP-2在倉鼠肝臟中的蛋白裂解，與在培養(yǎng)的細(xì)胞中的發(fā)現(xiàn)有些不同。資料表明SREBP-1和SREBP-2的裂解片段在倉鼠肝臟中的調(diào)節(jié)作用是不一致的。倉鼠肝臟經(jīng)mevinolin 加降膽寧處理后，SREBP-2的裂解片段增多，而SREBP-1的裂解片段減少。這一結(jié)果似乎表明在倉鼠肝臟中，SREBP-1對(duì)LDLR和HMGCoA合酶基因的基礎(chǔ)翻譯起作用，而SREBP-2對(duì)經(jīng)膽汁酸結(jié)合樹酯和膽固醇還原酶抑制物處理后，形成的膽固醇缺乏狀態(tài)的基因翻譯起作用。
另有報(bào)道，胰島素和類胰島素生長因子Ⅰ也可以通過SREBP-1介導(dǎo)LDL-R啟動(dòng)子的激活，從而調(diào)節(jié)細(xì)胞內(nèi)的膽固醇含量。
總之，在細(xì)胞內(nèi)膽固醇含量的自我平衡中，SREBPs起了重要作用，其詳細(xì)機(jī)制的闡明，必然對(duì)膽固醇代謝調(diào)節(jié)的研究產(chǎn)生重大影響。
(董學(xué)梅 滕思勇 鄭芳 崔天盆)
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