Free Cholesterol Bioavailability and Atherosclerosis.
Free Cholesterol Bioavailability and Atherosclerosis.
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DOI：
10.1007/s11883-022-01011-z
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发表时间：
2022-05
影响因子：
5.8
通讯作者：
Le, Nhat-Tu
中科院分区：
文献类型：
--
作者：
Abe, Rei J.;Abe, Jun-ichi;Nguyen, Minh T. H.;Olmsted-Davis, Elizabeth A.;Mamun, Abrar;Banerjee, Priyanka;Cooke, John P.;Fang, Longhou;Pownall, Henry;Le, Nhat-Tu
关键词：
高密度脂蛋白（HDL）既是胆固醇受体，又是胆固醇逆向转运（RCT）途径的载体，具有抗动脉粥样硬化作用。然而，目前增加血浆HDL胆固醇（HDL-c）浓度的药物疗法矛盾地未能预防或减少动脉粥样硬化和心血管疾病（CVD）。鉴于脂蛋白表面和细胞之间的游离胆固醇（FC）转移是可逆的，过量的血浆FC可以转移到外周组织部位的细胞中，导致动脉粥样硬化。在这里，我们总结了导致这种矛盾的潜在机制，并强调了过量游离胆固醇（FC）生物利用度在动脉粥样硬化与动脉粥样硬化保护中的作用。最近的研究结果已经建立了HDL-C浓度和动脉粥样硬化之间的复杂关系。全身性清道夫受体B 1型（SR-B1）敲除（KO）小鼠表现出饮食诱导的动脉粥样硬化增加，尽管与野生型（WT）小鼠相比血浆HDL-c浓度升高。与WT小鼠相比，SR-B1小鼠中HDL-FC的生物利用度更高，这与多种细胞类型和组织部位中的FC含量更高相关。这些结果表明，尽管HDL-C浓度高，但功能障碍的HDL与高FC生物利用度是atheroprone。过去对HDL-c参与胆固醇转运的过度简化导致了HDL靶向治疗的失败。有证据表明，FC介导的HDL功能比其数量更重要;因此，破译HDL-FC生物利用度可诱导动脉粥样硬化的调节机制可能具有深远的临床意义。
As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection. Recent findings have established a complex relationship between HDL-c concentration and atherosclerosis. Systemic scavenger receptor class B type 1 (SR-B1) knock out (KO) mice exhibit with increased diet-induced atherosclerosis despite having an elevated plasma HDL-c concentration compared to wild type (WT) mice. The greater bioavailability of HDL-FC in SR-B1 vs. WT mice is associated with a higher FC content in multiple cell types and tissue sites. These results suggest that dysfunctional HDL with high FC bioavailability is atheroprone despite high HDL-c concentration. Past oversimplification of HDL-c involvement in cholesterol transport has led to the failures in HDL targeted therapy. Evidence suggests that FC-mediated functionality of HDL is of higher importance than its quantity; as a result, deciphering the regulatory mechanisms by which HDL-FC bioavailability can induce atherosclerosis can have far-reaching clinical implications.
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影响因子：
4.4
作者：
Block, Robert C.;Dorsey, E. Ray;Beck, Christopher A.;Brenna, J. Thomas;Shoulson, Ira
通讯作者：
Shoulson, Ira
影响因子：
39.3
作者：
Chapman MJ;Le Goff W;Guerin M;Kontush A
通讯作者：
Kontush A
影响因子：
4.8
作者：
de Chaves, EIP;Rusiñol, AE;Vance, JE
通讯作者：
Vance, JE
DOI：
10.1161/atvbaha.114.304200
发表时间：
2014-11-01
影响因子：
8.7
作者：
Fuller, Mark;Dadoo, Omid;Trigatti, Bernardo L.
通讯作者：
Trigatti, Bernardo L.
影响因子：
2.9
作者：
Cerqueira, Nuno M. F. S. A.;Oliveira, Eduardo F.;Fernandes, P. A.
通讯作者：
Fernandes, P. A.