Adenovirus-mediated gene transfer as an in vivo probe of lipoprotein metabolism.
Adenovirus-mediated gene transfer as an in vivo probe of lipoprotein metabolism.
复制标题
腺病毒介导的基因转移作为脂蛋白代谢的体内探针。
DOI：
10.1161/01.cir.94.9.2046
复制
发表时间：
1996
期刊：
影响因子：
37.8
通讯作者：
Leiden,JM
中科院分区：
文献类型：
--
作者：
Leiden,JM
过去20年的大量流行病学研究告诉我们，血清高密度脂蛋白胆固醇水平与随后发生动脉粥样硬化性心脏病的风险之间存在着强烈的负相关关系。1 2 3然而，尽管最近在了解高密度脂蛋白代谢的生物化学和遗传学方面取得了很大进展，但高密度脂蛋白具有明显的抗动脉粥样硬化作用的分子和细胞机制仍不清楚。4高密度脂蛋白是一种不均匀的小(70~100Å)脂蛋白颗粒，由CE核心(含少量TG)组成，周围环绕着包含各种脂蛋白的磷脂单分子层和UC(图1)。4载脂蛋白AI和≈A-II是高密度脂蛋白的主要蛋白质组分，分别占高密度脂蛋白的70%和20%。一些高密度脂蛋白颗粒只含有载脂蛋白AI，而另一些颗粒同时含有载脂蛋白A-1和载脂蛋白A-II。如下所述，最近的数据表明，这两类高密度脂蛋白颗粒在抗动脉粥样硬化方面可能存在显著差异。5除载脂蛋白AI和载脂蛋白A-II外，高密度脂蛋白颗粒还含有少量的载脂蛋白A-IV、载脂蛋白E、载脂蛋白C和载脂蛋白D。高密度脂蛋白还与两种重要的脂转移蛋白有关：LCAT，催化UC和卵磷脂(磷脂酰胆碱)形成CE和溶血磷脂；CETP，促进CE从高密度脂蛋白向低密度脂蛋白和极低密度脂蛋白转移，以换取甘油三酯。此外，高密度脂蛋白颗粒在与肝脏脂肪酶相互作用后，其核心脂组成发生改变。盘状高密度脂蛋白颗粒主要包含磷脂、UC和载脂蛋白AI，从肠道和肝脏重新分泌，也通过脂解后从富含甘油三酯的脂蛋白(VLDL和乳胶微粒)表面释放的载脂蛋白和磷脂的结合在血浆中产生(图2)。新生的高密度脂蛋白颗粒的成熟包括从周围细胞和代谢的富含甘油三酯的脂蛋白中摄取UC，并通过与高密度脂蛋白相关的LCAT将其转化为CES。然后，这些CE被转移到高密度脂蛋白颗粒的核心，导致高密度脂蛋白的大小和脂肪含量显著增加，以及高密度脂蛋白的球状转变。人的高密度脂蛋白颗粒以两个主要峰的形式沉淀，称为高密度脂蛋白2和高密度脂蛋白3，它们的载脂蛋白AI和CE的含量不同。4与HDL3颗粒相比，较大的HDL2颗粒含有更多的CE和额外的载脂蛋白AI分子。因此，高密度脂蛋白的稳态浓度反映了合成和重塑事件以及分解代谢的复杂相互作用，后者涉及一种假定的高密度脂蛋白受体。
Numerous epidemiological studies over the past 20 years have taught us that there is a strong inverse correlation between the levels of serum HDL-C and the subsequent risk of atherosclerotic heart disease. 1 2 3 However, despite a great deal of recent progress in understanding the biochemistry and genetics of HDL metabolism, the molecular and cellular mechanisms underlying the apparent antiatherogenic effects of HDL remain unclear. 4 The HDLs are heterogeneous, small (70 to 100 Å) lipid-protein particles composed of a core of CE (with a small amount of TG) surrounded by a phospholipid monolayer containing a variety of lipoproteins and UC (Fig 1). 4 Apo AI and apo A-II are the major protein components of HDL, constituting≈ 70% and 20%, respectively, of the HDL protein. Some HDL particles contain only apo AI, whereas others contain both apo A-1 and apo A-II. As described below, recent data suggest that these two classes of HDL particles may differ significantly in their antiatherogenic potential. 5 6 HDL particles contain, in addition to apo AI and apo A-II, smaller amounts of apo A-IV, apo E, apo C, and apo D. HDL can also associate with two important lipid transfer proteins: LCAT, which catalyzes the formation of CE and lysolecithin from UC and lecithin (phosphatidyl choline), and CETP, which promotes the transfer of CEs from HDL to LDL and VLDL in exchange for TG. In addition, HDL particles undergo modification of their core lipid composition after interaction with hepatic lipase.Nascent discoidal HDL particles containing predominantly phospholipid, UC, and apo AI are secreted de novo from the intestine and liver and arise also in the plasma through the association of apolipoproteins and phospholipids liberated from the surface of TG-rich lipoproteins (VLDL and chylomicrons) after lipolysis 4 (Fig 2). The maturation of nascent HDL particles involves the uptake of UC from cells in the periphery and from metabolized TG-rich lipoproteins and its conversion to CEs by HDL-associated LCAT. These CEs are then displaced to the core of the HDL particles, resulting in both a significant increase in the size and lipid content and a spherical transformation of the HDL. Human HDL particles sediment as two major peaks, called HDL 2 and HDL 3, which differ in their contents of both apo AI and CE. 4 The larger HDL 2 particles contain significantly more CE and an additional apo AI molecule compared with the HDL 3 particles. The steady-state concentration of HDL thus reflects the complex interactions of synthetic and remodeling events together with catabolism, the latter involving a putative HDL receptor.
登录
查看更多内容
用重组腺病毒体内纠正渡边遗传性高脂血症兔的低密度脂蛋白受体缺陷。
影响因子：
4.8
作者：
Karen Kozarsky;D. R. McKinley;L. L. Austin;S. Raper;Leslie D. Stratford;J. M. Wilson
通讯作者：
J. M. Wilson
影响因子：
15.9
作者：
KASHYAP, VS;SANTAMARINAFOJO, S;BREWER, HB
通讯作者：
BREWER, HB
分子生物学对我们理解脂蛋白代谢和动脉粥样硬化病理学的影响。
影响因子：
--
作者：
T. Knecht;C. Glass
通讯作者：
C. Glass
影响因子：
2.9
作者：
CASTRO, GR;FIELDING, CJ
通讯作者：
FIELDING, CJ
影响因子：
15.9
作者：
ISHIBASHI, S;BROWN, MS;HERZ, J
通讯作者：
HERZ, J