Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems
Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems
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DOI：
10.1172/jci14011
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发表时间：
2001-09-01
影响因子：
15.9
通讯作者：
Krieger, M
中科院分区：
文献类型：
--
作者：
Krieger, M
j .中国。投资管理，2008,(3):1 - 4。DOI: 10.1172 / JCI200114011。命名为SR-BII)，两者都是脂肪酰化蛋白，在培养细胞中聚集在小窝样富含胆固醇的脂质结构域（见Febbraio等人，这个视角系列，参考文献10；也见参考文献11）。在SR-BI克隆后不久，它就被证明可以与AcLDL以外的多种配体结合，包括OxLDL、马来酰化BSA、阴离子磷脂、凋亡细胞以及未修饰的LDL和VLDL（11）。最引人注目和意想不到的发现是，SR-BI与HDL具有高亲和力（11,13），这提高了现在证实的可能性，即SR-BI代表了长期寻找的生理相关的HDL受体。与传统的低密度脂蛋白受体（LDLR）一样，SRBI通过首先介导脂蛋白与细胞外表面的结合，促进细胞从脂蛋白疏水核心吸收胆固醇（主要以胆固醇酯的形式）。然而，SR-BI在脂蛋白结合后的脂质摄取机制与LDLR明显不同。LDLR通过被包裹的小坑和小泡介导完整LDL颗粒的内吞作用，并随后在溶酶体中进行水解（14）。SR-BI介导高密度脂蛋白胆固醇酯的选择性摄取（11,13）。选择性摄取包括脂蛋白疏水核心的胆固醇酯有效地转移到细胞中，而不是脂蛋白表面的载脂蛋白。它不涉及完整脂蛋白颗粒的连续内化及其随后的降解。大约20年前，Glass等人和Stein等人在对血浆高密度脂蛋白脂质和蛋白质成分进行差异放射性标记的组织清除研究中，首次发现了主要由肝脏和甾体源性组织进行的体内选择性脂质摄取（参考文献11）。sr - bi介导的选择性脂质摄取似乎是一个两步过程，其中高亲和力脂蛋白结合之后是受体介导的脂质从脂蛋白颗粒转移到细胞膜（参考文献11）。脂质转移后，脂质耗尽的脂蛋白颗粒从细胞中释放出来并重新进入细胞外空间。尽管srbi依赖性细胞胆固醇外排的生理意义尚未确定，但SR-BI还可以介导高密度脂蛋白和细胞之间未酯化胆固醇和磷脂的双向流动。SR-BI可以作为LDL受体（结合和选择性摄取）以及HDL受体发挥作用（参考文献11）。CD36也可以结合HDL和LDL，但它不能有效地介导胆固醇酯的摄取（参见文献11）。sr - bi介导的选择性脂质摄取的详细分子机制尚未阐明。一些技术已经被用来证明LDL和HDL在SR-BI上有不同的结合模式和可能不同的结合位点（11,15,16）。引人注目的是，HDL有效地竞争LDL与SR-BI的结合，而LDL只能部分竞争HDL与SR-BI的结合（13）。这种现象被称为“非互惠交叉竞争”（NRCC），在SR-AI和SR-AII的研究中也有记载（17）。在NRCC中，一种配体有效地竞争第二种配体的结合，而第二种配体无法竞争或仅部分竞争第一种配体的结合。配体之间NRCC的观察可能表明该受体携带多个结合位点，具有不同的配体结合特性。如果配体结合没有达到平衡，NRCC也可能在生理学相关的实验条件下（或推测在体内条件下）被观察到。然而……
J. Clin. Invest. 108: 793–797 (2001). DOI: 10.1172/JCI200114011. designated SR-BII), and both are fatty acylated proteins that cluster in caveola-like cholesterol-rich lipid domains in cultured cells (see Febbraio et al., this Perspective series, ref. 10; see also ref. 11). Shortly after SR-BI was cloned, it was shown to bind to a variety of ligands other than AcLDL, including OxLDL, maleylated BSA, anionic phospholipids, apoptotic cells, and unmodified LDL and VLDL (11). The most striking and unexpected finding was that SR-BI binds HDL with high affinity (11, 13), raising the possibility, now confirmed, that SR-BI represented a longsought physiologically relevant HDL receptor. As is the case for the classic LDL receptor (LDLR), SRBI facilitates the cellular uptake of cholesterol (primarily in the form of cholesteryl esters) from the hydrophobic cores of lipoproteins by first mediating the binding of the lipoprotein to the outer surfaces of the cells. However, the mechanism of lipid uptake following lipoprotein binding for SR-BI differs markedly from that of the LDLR. The LDLR mediates endocytosis of the intact LDL particle via coated pits and vesicles, and its subsequent hydrolysis in lysosomes (14). SR-BI mediates the selective uptake of HDL’s cholesteryl esters (11, 13). Selective uptake involves efficient transfer to cells of the cholesteryl esters from the lipoprotein’s hydrophobic core, but not the apolipoprotein at the lipoprotein’s surface. It does not involve the sequential internalization of the intact lipoprotein particle and its subsequent degradation. Selective lipid uptake in vivo, primarily by the liver and steroidogenic tissues, was first identified almost 20 years ago by Glass et al. and Stein et al. during tissue clearance studies of plasma HDL differentially radiolabeled on both its lipid and protein components (reviewed in ref. 11).SR-BI–mediated selective lipid uptake appears to be a two-step process, in which high-affinity lipoprotein binding is followed by receptor-mediated transfer of lipid from the lipoprotein particle to the cell membrane (reviewed in ref. 11). After lipid transfer, the lipiddepleted lipoprotein particle is released from the cells and re-enters the extracellular space. SR-BI can also mediate the bidirectional flux of unesterified cholesterol and phospholipids between HDL and cells, although the physiologic significance of SRBI–dependent cellular cholesterol efflux has not been established. SR-BI can function as an LDL receptor (binding and selective uptake) as well as an HDL receptor (reviewed in ref. 11). CD36 can also bind HDL and LDL, but it cannot efficiently mediate cholesteryl ester uptake (reviewed in ref. 11). The detailed molecular mechanism underlying SR-BI–mediated selective lipid uptake has not yet been elucidated. Several techniques have been used to show that there are distinct modes of binding and perhaps distinct binding sites for LDL and HDL on SR-BI (11, 15, 16). Strikingly, HDL competes effectively for the binding of LDL to SR-BI, whereas LDL can only partially compete for HDL binding to SR-BI (13). This phenomenon, termed “nonreciprocal cross-competition”(NRCC), has been documented in studies of SR-AI and SR-AII as well (17). In NRCC, one ligand efficiently competes for the binding of a second ligand whereas the second ligand fails to compete, or competes only partially, for the binding of the first. The observation of NRCC between ligands probably indicates that the receptor carries multiple binding sites with differing ligand binding properties. NRCC might also be observed under physiologically relevant experimental conditions (or, presumably, in vivo conditions) if ligand binding does not proceed to equilibrium. However it …