Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I.
Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I.
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发表时间：
1999-07
影响因子：
6.5
通讯作者：
X. Collet;A. Tall;H. Serajuddin;K. Guendouzi;L. Royer;H. Oliveira;R. Barbaras;Xian-Cheng Jiang;O. Francone
中科院分区：
文献类型：
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作者：
X. Collet;A. Tall;H. Serajuddin;K. Guendouzi;L. Royer;H. Oliveira;R. Barbaras;Xian-Cheng Jiang;O. Francone
HDL胆固醇酯（CE）从血浆转运至肝脏涉及由肝清道夫受体B-I（SR-BI）介导的直接摄取途径和涉及通过胆固醇酯转移蛋白（CETP）将HDL CE交换为富含TG的脂蛋白的甘油三酯（TG）的间接途径。我们在表达人CETP和/或人卵磷脂：胆固醇酰基转移酶（LCAT）转基因的小鼠中进行了HDL CE周转研究，背景是人apoA-I表达。LCAT转基因延迟了肝脏对HDL CE的清除率，而CETP转基因则增加了肝脏对HDL CE的清除率。然而，在表达CETP的小鼠中，HDL CE放射性并没有增加转移到富含TG的脂蛋白组分中，这表明肝脏对HDL CE的直接清除增加。为了评估这可能由SR-BI介导的可能性，将从不同组转基因小鼠的血浆中分离的HDL与SR-BI转染的或对照CHO细胞一起孵育。与来自缺乏CETP的小鼠的HDL相比，从表达CETP的小鼠分离的HDL显示SR-BI介导的HDL CE摄取增加2至4倍。在细胞培养物中向HDL中添加纯CETP不会导致细胞对HDL CE的选择性摄取增加。然而，当人HDL富含TG孵育富含TG的脂蛋白在CETP的存在下，然后用肝脂肪酶处理，有一个显着增强HDL CE摄取。因此，通过CETP重塑人HDL，涉及CE 1-TG互换，随后通过肝脂肪酶（HL）的作用，导致细胞SR-BI对HDL CE的摄取增强。这些观察结果表明，在人类等选择性吸收和CETP途径均活跃的动物中，这两种途径可以协同作用，增强胆固醇反向转运。
The transport of HDL cholesteryl esters (CE) from plasma to the liver involves a direct uptake pathway, mediated by hepatic scavenger receptor B-I (SR-BI), and an indirect pathway, involving the exchange of HDL CE for triglycerides (TG) of TG-rich lipoproteins by cholesteryl ester transfer protein (CETP). We carried out HDL CE turnover studies in mice expressing human CETP and/or human lecithin:cholesterol acyltransferase (LCAT) transgenes on a background of human apoA-I expression. The fractional clearance of HDL CE by the liver was delayed by LCAT transgene, while the CETP transgene increased it. However, there was no incremental transfer of HDL CE radioactivity to the TG-rich lipoprotein fraction in mice expressing CETP, suggesting increased direct removal of HDL CE in the liver. To evaluate the possibility that this might be mediated by SR-BI, HDL isolated from plasma of the different groups of transgenic mice was incubated with SR-BI transfected or control CHO cells. HDL isolated from mice expressing CETP showed a 2- to 4-fold increase in SR-BI-mediated HDL CE uptake, compared to HDL from mice lacking CETP. The addition of pure CETP to HDL in cell culture did not lead to increased selective uptake of HDL CE by cells. However, when human HDL was enriched with TG by incubation with TG-rich lipoproteins in the presence of CETP, then treated with hepatic lipase, there was a significant enhancement of HDL CE uptake. Thus, the remodeling of human HDL by CETP, involving CE;-TG interchange, followed by the action of hepatic lipase (HL), leads to the enhanced uptake of HDL CE by cellular SR-BI. These observations suggest that in animals such as humans in which both the selective uptake and CETP pathways are active, the two pathways could operate in a synergistic fashion to enhance reverse cholesterol transport.