B族Ⅰ型清道夫受体与高密度脂蛋白代谢

B族Ⅰ型清道夫受体(SR-BI)是高密度脂蛋白(HDL)的受体,能够介导HDL胆固醇酯(CE)的选择性吸收。SR-BI介导的选择性吸收分为两个步骤:第一步是SR-BI和HDL结合;第二步胆固醇酯转移到胞膜。关于此过程已经提出了3种模型:①脂质融合;②疏水通道;③细胞内吞。进一步明确SR-BI介导的脂质吸收的过程与机制对胆固醇逆转运以及动脉粥样硬化的研究有重要意义。     

B类清道夫受体I与脂质的选择性吸收

B类清道夫受体I(scavenger receptor class B type I,SR-BI)是最先被确定的高密度脂蛋白(HDL)受体。它与CD36一样属于多配体受体,能够直接与多种蛋白质和脂质发生作用。SR-BI可以介导细胞膜上脂质的双向转运,即脂质选择性摄取和胆固醇的流出。脂质的选择性吸收与传统意义上的低密度脂蛋白(LDL)受体所介导的内吞明显不同,选择性吸收是指脂蛋白中的脂质被选择性吸收,而脂蛋白成分可释放再利用的过程[1],LDL受体介导的是脂蛋白与脂质均被内吞入细胞的过程。本文就SR-BI在脂质选择性吸收中的作用及其调节作一综述。     

高密度脂蛋白对炎症状态下脂肪细胞胆固醇流出的影响

目的:探讨高密度脂蛋白(High-density lipoprotein,HDL)对体外模拟脂肪细胞炎症状态下胆固醇流出的保护作用及其机制.方法:将前脂肪细胞株3T3-LI(3T3-L1)诱导分化成为成熟的脂肪细胞后,作为空白对照组,脂肪细胞以脂多糖(LPS,100 ng/ml)刺激6小时,为LPS组;脂肪细胞经LPS( 100ng/ml)刺激6小时后,分别用不同浓度HDL孵育16小时,为10 μg/ml HDL+LPS组、50μg/ml HDL+LPS组、100 μg/ml HDL+LPS组.采用液体闪烁计数器检测不同浓度的HDL对LPS刺激的脂肪细胞胆固醇流出的影响,并检测细胞内B族I型清道夫受体(SR-BI)信使核糖核酸(mRNA)和蛋白表达水平.结果:LPS组的胆固醇流出率(2.5±0.6)％较空白对照组(4.1±0.4)％减少,3种不同浓度的HDL+LPS组干预后细胞胆固醇流出率较LPS组增加;LPS组SR-BI mRNA和蛋白表达较空白对照组降低,与LPS组相比较,3种不同浓度的HDL+LPS组SR-BI mRNA和蛋白表达随HDL浓度的增加而递增,差异均有统计学意义(P＜0.05).结论:炎症状态下脂肪细胞的胆固醇流出减少,通过上调SR-BI表达能促进炎性脂肪细胞内胆固醇的流出,减少胆固醇在脂肪细胞内的蓄积.该作用可能与其促进脂肪细胞表达SR-BI有关.     

高密度脂蛋白靶向防治动脉粥样硬化新进展

许多随机临床试验已经明确,他汀类药物因为可以降低低密度脂蛋白胆固醇水平并轻度增加高密度脂蛋白胆固醇(HDLC)水平,已经成为防治动脉粥样硬化(As)疾病的主要标准疗法。高密度脂蛋白(HDL)颗粒介导的胆固醇逆转运(RCT)途径具有抗As的作用。目前HDL靶向治疗的重要途径已经不是升高HDLC水平,更多的是通过改善HDL功能,增强血浆胆固醇的清除,以及预防和减轻与As有关的炎症。胆固醇酯转移蛋白抑制剂可增加正常或低HDLC患者的HDLC水平;肝X受体激动剂可通过增加RCT减少As;使用重组HDL的HDL治疗在动物模型中显著有效;在细胞以及动物模型中研究发现,通过干预某些基因靶点,可使HDLC的水平和HDL功能得到改善。回顾相关文献,我们认为:HDL靶向治疗有防治As的潜力,可能对心血管疾病患者有效。     

高密度脂蛋白受体研究

高密度脂蛋白(HDL)与动脉粥样硬化及冠心病的发生率呈负相关,提示HDL在动脉粥样硬化发生中起保护性作用。HDL的抗动脉粥样硬化作用,可能主要通过抑制低密度脂蛋白(LDL)及其胆固醇被动脉壁细胞摄取、沉积,转运外周组织中的胆固醇至肝脏分解代谢来实现。这过程可能是通过HDL的特异性受     

B族I型清道夫受体与高密度脂蛋白代谢

B族I型清道夫受体（SR—BI）是高密度脂蛋白（HDL）的受体，能够介导HDL胆固醇酯（CE）的选择性吸收。SR-BI介导的选择性吸收分为两个步骤：第一步是SR—BI和HDL结合；第二步胆固醇酯转移到胞膜。关于此过程已经提出了3种模型：①脂质融合；②疏水通道；③细胞内吞。进一步明确SR—BI介导的脂质吸收的过程与机制对胆固醇逆转运以及动脉粥样硬化的研究有重要意义。     

ATP结合ABCA1在动脉粥样硬化性疾病发生发展中的作用机制研究进展

动脉粥样硬化(As)是导致各种血管疾病的主要原因,而过多的胆固醇在巨噬细胞中积累形成泡沫细胞是As的主要原因之一,ATP结合盒转运体A1(ABCA1)是高密度脂蛋白(HDL)和胆固醇逆转运(RCT)的重要调节因子。综述ABCA1在As性疾病发生发展中的作用机制发现,ABCA1可以抑制As的炎症反应,引起血管内皮细胞变化,参与氧化应激反应,通过多种代谢通路影响As。     

B类Ⅰ型清道夫受体与胆固醇的双向转运

B类Ⅰ型清道夫受体是一种细胞膜的糖蛋白,具有广泛的配基识别谱,在多种组织中高度表达。它是一种高密度脂蛋白(HDL)的高亲和力受体,在细胞水平上介导高密度脂蛋白和低密度脂蛋白选择性摄取胆固醇酯。在介导游离胆固醇的双向转运,参与动脉壁胆固醇的清除中起着重要作用。     

动脉粥样硬化研究的新靶点:B族Ⅰ型清道夫受体

B族Ⅰ型清道夫受体(SRBI)作为高密度脂蛋白(HDL)受体,能与HDL结合,参与HDL胆固醇酯的选择性摄取和代谢,以及介导游离胆固醇在脂蛋白和细胞之间的双向运动,并通过多种机制对动脉粥样硬化的发生起保护性作用。体内SRBI功能的分析不仅证实了SRBI在HDL代谢中的重要性,而且也为研究动脉粥样硬化发生机制提供了一种新的动物模型。     

B类I型清道夫受体与胆固醇的双向转运

B类I型清道夫受体是一种细胞膜的糖蛋白,具有广泛的配基识别谱,在多种组织中高度表达.它是一种高密度脂蛋白(HDL)的高亲和力受体,在细胞水平上介导高密度脂蛋白和低密度脂蛋白选择性摄取胆固醇酯.在介导游离胆固醇的双向转运,参与动脉壁胆固醇的清除中起着重要作用.     

SR-BI and HDL cholesteryl ester metabolism

Scavenger receptor class B, type I (SR-BI) is the receptor for high density lipoprotein (HDL) that mediates cellular uptake of HDL cholesteryl ester (CE) and is a major route for cholesterol delivery to steroidogenic pathways. SR-BI is localized in specialized microvillar channel plasma membrane compartments that retain HDL and are sites for HDL CE selective uptake. In fact, adrenal gland microvillar channel formation is regulated by adrenocorticotropin hormone and requires SR-BI expression. SR-BI-mediated uptake of HDL CE is a two-step process requiring high affinity HDL binding followed by transfer of CE to the membrane. SR-BI delivers HDL CE to sites in the membrane where it is readily metabolized to free cholesterol by cell type-specific neutral CE hydrolases. The most likely candidate for the hydrolysis of HDL CE delivered via SR-BI in the adrenal gland is hormone sensitive lipase. New data in adrenocortical cells as well as the study of a mutant SR-BI receptor lend insight into the mechanism of cholesterol transfer from plasma HDL to the steroidogenic pathway in endocrine cells.     

Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology.

The high density lipoprotein (HDL) receptor SR-BI (scavenger receptor class B type I) mediates the selective uptake of plasma HDL cholesterol by the liver and steroidogenic tissues. As a consequence, SR-BI can influence plasma HDL cholesterol levels, HDL structure, biliary cholesterol concentrations, and the uptake, storage, and utilization of cholesterol by steroid hormone-producing cells. Here we used homozygous null SR-BI knockout mice to show that SR-BI is required for maintaining normal biliary cholesterol levels, oocyte development, and female fertility. We also used SR-BI/apolipoprotein E double homozygous knockout mice to show that SR-BI can protect against early-onset atherosclerosis. Although the mechanisms underlying the effects of SR-BI loss on reproduction and atherosclerosis have not been established, potential causes include changes in (i) plasma lipoprotein levels and/or structure, (ii) cholesterol flux into or out of peripheral tissues (ovary, aortic wall), and (iii) reverse cholesterol transport, as indicated by the significant reduction of gallbladder bile cholesterol levels in SR-BI and SR-BI/apolipoprotein E double knockout mice relative to controls. If SR-BI has similar activities in humans, it may become an attractive target for therapeutic intervention in a variety of diseases.     

SR-BI-mediated HDL cholesteryl ester delivery in the adrenal gland

In adrenocortical cells, scavenger receptor class B, type I (SR-BI) is localized in specialized plasma membrane compartments, called microvillar channels, that retain high density lipoprotein particles (HDL) and are sites for the selective uptake of cholesteryl esters (CE). Formation of microvillar channels is regulated by adrenocorticotropic hormone (ACTH) and requires SR-BI expression. Subsequent to SR-BI-mediated delivery to the plasma membrane, HDL-CE is metabolized to free cholesterol by hormone sensitive lipase and transported to the mitochondria for steroid synthesis via START domain proteins. The relevance of SR-BI to adrenal steroidogenesis is evident by the impairment of glucocorticoid-mediated stress response in the absence of SR-BI-mediated HDL-CE uptake in mice. On the molecular level, SR-BI mediates HDL-CE selective uptake by forming a hydrophobic channel. In addition, SR-BI facilitates bi-directional flux of cholesterol by modifying the phospholipid content of the plasma membrane. SR-BI most likely accomplishes these functions by forming homo-oligomers in the plasma membrane. Examination of SR-BI oligomerization using fluorescence resonance energy transfer spectroscopy revealed that SR-BI multimerizes via its C-terminal region. Overall, SR-BI is the cell surface receptor responsible for selective uptake of lipoprotein cholesterol and its ultimate delivery to sites of hormone synthesis in steroidogenic tissues.     

Scavenger receptor type BI potentiates reverse cholesterol transport system by removing cholesterol ester from HDL

High-density lipoprotein (HDL) plays an important role in reverse cholesterol transport by removing accumulated cholesterol from extrahepatic tissues. Subsequently, cholesterol ester (CE) on HDL in humans is transported to apolipoprotein B-containing lipoproteins by cholesteryl ester transfer protein (CETP). CETP deficiency, which is common in the Japanese population, leads to a marked increase in HDL-cholesterol levels due to impaired CE transport from HDL to LDL. It has been reported that the HDL observed in CETP deficiency is an atherogenic lipoprotein, as it contains a large amount of CE. Scavenger receptor class B type I (SR-BI) has been found to be an authentic HDL receptor that mediates the selective uptake of HDL CE and the bi-directional transfer of free cholesterol between HDL and cells. In the present study, the interaction between SR-BI and CE-rich HDL from CETP-deficient patient was studied in order to evaluate the anti-atherosclerotic role of SR-BI in relation to CE uptake and reverse cholesterol transport. When CE-rich HDL was added to the medium of SR-BI-transfected CHO (SR-BI CHO) cells, more CE accumulated in SR-BI CHO cells compared to control HDL. In contrast, the amount of cholesterol efflux from SR-BI CHO cells into HDL was almost the same between the two HDLs. Therefore, when CE-rich HDL was added to the medium of SR-BI CHO cells, the intracellular CE content increased significantly. Moreover, the particle size of HDL in CETP-deficient patient decreased significantly when the HDL was added to the medium of SR-BI CHO cells, and this HDL showed an increment of CE efflux from foam cells. These results indicate that SR-BI reduces the cholesterol content and size of the CE-rich HDL from CETP deficiency, which ultimately activate reverse cholesterol transport system.     

Advanced glycation end products (AGE) inhibit scavenger receptor class B type I-mediated reverse cholesterol transport: a new crossroad of AGE to cholesterol metabolism

Advanced glycation end products (AGE) -modified proteins behave as active ligands for several receptors belonging to the scavenger receptor family. Scavenger receptor class B type I (SR-BI) was identified as the first high density lipoprotein (HDL) receptor that mediates selective uptake of HDL-cholesteryl esters (HDL-CE). This study investigated whether AGE proteins serve as ligands for SR-BI and affect SR-BI-mediated cholesterol transport using Chinese hamster ovary (CHO) cells overexpressing hamster SR-BI (CHO-SR-BI cells). [125I] AGE-bovine serum albumin (AGE-BSA) underwent active endocytosis and subsequent lysosomal degradation by CHO-SR-BI cells, indicating that SR-BI serves as an AGE receptor. SR-BI-mediated selective uptake of HDL-CE by CHO-SR-BI cells was efficiently inhibited by AGE-BSA although AGE-BSA had no effect on HDL binding to CHO-SR-BI cells. In addition, AGE-BSA significantly inhibited the efflux of [3H] cholesterol from CHO-SR-BI cells to HDL. These findings suggest the possibility that AGE proteins in the circulation interfere with the functions of SR-BI in reverse cholesterol transport by inhibiting the selective uptake of HDL-CE, as well as cholesterol efflux from peripheral cells to HDL, thereby accelerating diabetes-induced atherosclerosis.     

Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol

Scavenger receptor BI (SR-BI) is a cell surface receptor that binds high density lipoproteins (HDL) and mediates selective uptake of HDL cholesteryl esters (CE) in transfected cells. To address the physiological role of SR-BI in HDL cholesterol homeostasis, mice were generated bearing an SR-BI promoter mutation that resulted in decreased expression of the receptor in homozygous mutant (designated SR-BI att) mice. Hepatic expression of the receptor was reduced by 53% with a corresponding increase in total plasma cholesterol levels of 50–70% in SR-BI att mice, attributable almost exclusively to elevated plasma HDL. In addition to increased HDL-CE, HDL phospholipids and apo A-1 levels were elevated, and there was an increase in HDL particle size in mutant mice. Metabolic studies using HDL bearing nondegradable radiolabels in both the protein and lipid components demonstrated that reducing hepatic SR-BI expression by half was associated with a decrease of 47% in selective uptake of CE by the liver, and a corresponding reduction of 53% in selective removal of HDL-CE from plasma. Taken together, these findings strongly support a pivotal role for hepatic SR-BI expression in regulating plasma HDL levels and indicate that SR-BI is the major molecule mediating selective CE uptake by the liver. The inverse correlation between plasma HDL levels and atherosclerosis further suggests that SR-BI may influence the development of coronary artery disease.     

Expression of scavenger receptor class B type 1 (SR-BI) promotes microvillar channel formation and selective cholesteryl ester transport in a heterologous reconstituted system

In the "selective" cholesteryl ester (CE) uptake process, surface-associated lipoproteins [high density lipoprotein (HDL) and low density lipoprotein] are trapped in the space formed between closely apposed surface microvilli (microvillar channels) in hormone-stimulated steroidogenic cells. This is the same location where an HDL receptor (SR-BI) is found. In the current study, we sought to understand the relationship between SR-BI and selective CE uptake in a heterologous insect cell system. Sf9 (Spodoptera frugiperda) cells overexpressing recombinant SR-BI were examined for (i) SR-BI protein by Western blot analysis and light or electron immunomicroscopy, and (ii) selective lipoprotein CE uptake by the use of radiolabeled or fluorescent (BODIPY-CE)-labeled HDL. Noninfected or infected control Sf9 cells do not express SR-BI, show microvillar channels, or internalize CEs. An unexpected finding was the induction of a complex channel system in Sf9 cells expressing SR-BI. SR-BI-expressing cells showed many cell surface double-membraned channels, immunogold SR-BI, apolipoprotein (HDL) labeling of the channels, and high levels of selective HDL-CE uptake. Thus, double-membraned channels can be induced by expression of recombinant SR-BI in a heterologous system, and these specialized structures facilitate both the binding of HDL and selective HDL-CE uptake.