第五节 胆固醇调节元件结合蛋白
胆固醇调节元件结合蛋白(SREBPs)，是一类能与胆固醇调节元件1(SRE-1)发生特异性结合的“碱性螺旋-环-螺旋-亮氨酸拉链”(bHLH-ZZP)蛋白。在细胞内缺乏胆固醇的情况下，SREBPs通过和SRE-1的结合，激活SRE-1的基因，使其翻译增强，发挥生理功能。
一、胆固醇调节元件1的功能和定位
编码低密度脂蛋白受体(LDL-R)的基因5'侧翼区，具有一个长10个碱基对的胆固醇调节元件1(sterol regulatory element 1,SRE-1)。SRE-1是一个条件正性调节元件，仅在细胞内胆固醇缺乏的条件下，才被激活。在其他的胆固醇调节基因如羟甲基戊二酸单酰CoA合酶(HMGCoA synthase )基因的启动子中也含有SRE-1，而在羟甲基戊二酸单酰CoA还原酶(HMGCoA reductase )基因的启动子中含有类似于SRE-1的胆固醇调节元件(SRE)。SRE-1通过调节LDL-R基因、HMGCoA合酶基因的翻译，控制细胞对外源性胆固醇的摄取量和内源性胆固醇的合成速率，调节细胞内胆固醇含量。SRE-1在LDL-R基因5'侧翼区的定位见图7-9。
图7-9 +1表示翻译起始位点，T/A表示TATA盒，空心箭头表示重复区，重复区1、重复区3可能和Sp1(一种正性翻译因子)结合。重复区2内含有SRE-1。
二、SREBPs的发现和命名
1989年，Tripathi B.Rajavashisth发现了一种能和SRE结合的锌脂蛋白。1993年，Michael R.Briggs等人，利用离子交换层析、凝胶过滤和DNA亲和层析的方法，从人类宫颈癌细胞(Hela细胞)核的提取物中分离出了这一组能与SRE-1结合的蛋白质，并将其命名为胆固醇调节元件结合蛋白(sterol regulatory element-binding proteins, SREBPs)。SREBPs在细胞胆固醇缺乏的情况下，通过和SRE-1的结合，激活LDLR基因、HMGCoA合酶基因的翻译。
三、SREBPs的结构和分类
SREBPs具有“碱性螺旋-环-螺旋-亮氨酸拉链”(basic helix-loop-helix-leucine zipper, bHLH-ZIP)结构，是bHLH-ZIP蛋白系列的一种。bHLH-ZIP蛋白包含一系列能特异性地和含E盒(E box, CANNTG)的DNA结合的蛋白质，例如：调节免疫球蛋白基因翻译的TFE3，致肿瘤蛋白Myc等。SREBPs虽是bHLH-ZIP蛋白中的一种，但又不同于其他的bHLH-ZIP蛋白。一方面，SREBPs分子量大，含1140个左右的氨基酸残基；另一方面，SREBPs不识别E盒(E box)而特定地识别SRE-1中直接重复的“CAC”序列。
迄今为止，发现有两种SREBPs。一种称SREBP-1，另一种称SREBP-2 。SREBP-1又由于其mRNA剪接方式的不同，以三种功能上完全相同，组成上略有不同的形式大量存在，这三种形式的蛋白分别称为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为例来描述SREBP-1。SREBP-1a含1147个氨基酸残基。分子量为125kD。至今，还没有发现SREBP-2存在多种不同的剪接后蛋白。SREBP-2含1141个氨基酸残基，分子量为121kD，与SREBP-1a之间有47%的同源性，含高度保守的bHLH-ZIP区，和SREBP-1a的bHLH-ZIP区有71%的一致性。但是SREBP-2含有不同SREBP-1a的谷氨酸富集区(在121个氨基酸残基中含多于27%的谷氨酸残基。SREBP-1a和SREBP-2的氨基酸序列和功能域结构之间的比较参见图7-10(A、B、C)。
图7-10 A：SREBP-2和SREBP-1a氨基酸序列之间的比较
“--”表示二者的相同部分
图7-10 B：SREBP-2和SREBP-1a的bHLH区(粗横线所示)的比较
四、SREBPs的生理功能
两种SREBPs利用位于其氨基酸残基470～570之间的疏水序列，附着于内质网膜和核膜，在氨基端的470个氨基酸残基组成的肽链中，均含“碱性螺旋-环-螺旋-亮氨酸拉链”的核心结构，使蛋白质能形成均一二聚体，并能和SRE-1结合。两种蛋白质氨基端一侧的结构中，都有酸性区域，可能作为DNA翻译的增强子。当人或仓鼠细胞在缺乏胆固醇的环境中培养时，蛋白酶在亮氨酸拉链和膜间的附着区处裂解SREBPs，并从膜上释放出水溶性的氨基端的裂解片段，这一片段约含470个氨基酸残基，表现分子量为68kD。这一片段能够移行入胞核，结合于SRE-1，从而激活LDLR基因翻译和HMGCoA合酶基因翻译。
SREBPs裂解、移行入胞核，进而结合于SRE-1，以致激活LDLR基因、HMGCoA合酶基因，都有赖于细胞内缺乏胆固醇。因为胆固醇能够抑制SREBPs的裂解。而已形成的SREBPs的裂解片段又很容易被迅速分解，从细胞核中快速消失。故而胆固醇的存在，将阻断整个调节通路，使SRE-1失活。
将SREBP-1和SREBP-2进行cDNAg隆，并采用质粒转染动物细胞的方法，使培养细胞，如Hela细胞和中国仓鼠卵巢细胞(CHO细胞)，表达SREBP-1和SREBP-2，发现他们调节细胞内胆固醇代谢的过程是一致的，功能上是协同的，然而两种蛋白质是单独发生作用，没有发现杂化二聚体。为什么存在这两种组成不同但功能一致的SREBPs，原因还不清楚。
研究仓鼠肝脏中产生的，由细胞内胆固醇含量调节的mRNA(包括LDLR和HMGCoA合酶的mRNA)的含量。肝脏经HMGCoA还原酶抑制物mevinolin处理后，这两种mRNA的量都增加。通过阻止胆固醇的合成，mevinolin诱导暂时的胆固醇水平降低，而增强胆固醇调节基因的翻译。当mevinolin和胆汁酸结合树酯，如降胆灵合用时，mevinolin增强翻译的效果更强。降胆宁通过阻止肠道对胆汁酸的再吸收，使胆固醇转变为胆汁酸，因而增加肝脏对胆固醇的进一步需求。
最近，研究HMGCoA还原酶抑制物和胆汁酸结合树酯是否促进SREBP-1和SREBP-2在仓鼠肝脏中的蛋白裂解，与在培养的细胞中的发现有些不同。资料表明SREBP-1和SREBP-2的裂解片段在仓鼠肝脏中的调节作用是不一致的。仓鼠肝脏经mevinolin 加降胆宁处理后，SREBP-2的裂解片段增多，而SREBP-1的裂解片段减少。这一结果似乎表明在仓鼠肝脏中，SREBP-1对LDLR和HMGCoA合酶基因的基础翻译起作用，而SREBP-2对经胆汁酸结合树酯和胆固醇还原酶抑制物处理后，形成的胆固醇缺乏状态的基因翻译起作用。
另有报道，胰岛素和类胰岛素生长因子Ⅰ也可以通过SREBP-1介导LDL-R启动子的激活，从而调节细胞内的胆固醇含量。
总之，在细胞内胆固醇含量的自我平衡中，SREBPs起了重要作用，其详细机制的阐明，必然对胆固醇代谢调节的研究产生重大影响。
(董学梅 滕思勇 郑 芳 崔天盆)
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