A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism
A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism
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DOI：
10.1073/pnas.94.23.12610
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发表时间：
1997-11-11
影响因子：
11.1
通讯作者：
Krieger, M
中科院分区：
文献类型：
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作者：
Rigotti, A;Trigatti, BL;Krieger, M
防止动脉粥样硬化的血浆高密度脂蛋白（HDL）被认为从外周组织中去除胆固醇并通过选择性摄取途径将胆固醇酯递送至肝脏（胆固醇逆向转运）和类固醇生成组织（例如，尽管其在生理和病理生理上的重要性，HDL的细胞代谢尚未得到很好的定义。已经提出B类I型清道夫受体（SR-BI）在HDL代谢中起重要作用，因为（i）它是介导培养细胞中选择性胆固醇摄取的细胞表面HDL受体，（ii）其生理调节表达在肝脏和类固醇生成组织中最丰富，和（iii）肝脏过表达显著降低血浆HDL。为了直接测试SR-BI在HDL代谢中的正常作用，我们产生了在SR-BI基因中具有靶向无效突变的小鼠。在杂合和纯合突变体中，相对于野生型对照，血浆胆固醇浓度分别增加了约31%和125%，因为形成了大的含载脂蛋白A-I（apoA-I）的颗粒，肾上腺胆固醇含量分别降低了42%和72%。这与脂蛋白大小的增加相结合，表明突变体中血浆胆固醇的增加是由于选择性胆固醇摄取的减少，这些结果为编码SR-BI的基因在小鼠血浆脂蛋白胆固醇水平的决定中起关键作用的提议提供了强有力的支持如果SR-BI在控制人类血浆HDL中具有类似的作用，则SR-BI可能影响动脉粥样硬化的发展和进展，并且可能是用于该疾病的治疗干预的有吸引力的候选者。
Plasma high density lipoprotein (HDL), which protects against atherosclerosis, is thought to remove cholesterol from peripheral tissues and to deliver cholesteryl esters via a selective uptake pathway to the liver (reverse cholesterol transport) and steroidogenic tissues (e.g., adrenal gland for storage and hormone synthesis), Despite its physiologic and pathophysiologic importance, the cellular metabolism of HDL has not been well defined. The class B, type I scavenger receptor (SR-BI) has been proposed to play an important role in HDL metabolism because (i) it is a cell surface HDL receptor which mediates selective cholesterol uptake in cultured cells, (ii) its physiologically regulated expression is most abundant in the liver and steroidogenic tissues, and (iii) hepatic overexpression dramatically lowers plasma HDL. To test directly the normal role of SR-BI in HDL metabolism, we generated mice with a targeted null mutation in the SR-BI gene. In heterozygous and homozygous mutants relative to wild-type controls, plasma cholesterol concentrations were increased by approximate to 31% and 125%, respectively, because of the formation of large, apolipoprotein A-I (apoA-I)-containing particles, and adrenal gland cholesterol content decreased by 42% and 72%, respectively, The plasma concentration of apoA-I, the major protein in HDL, was unchanged in the mutants, This, in conjunction with the increased lipoprotein size, suggests that the increased plasma cholesterol in the mutants was due to decreased selective cholesterol uptake, These results provide strong support for the proposal that in mice the gene encoding SR-BI plays a key role in determining the levels of plasma lipoprotein cholesterol (primarily HDL) and the accumulation of cholesterol stores in the adrenal gland, If it has a similar role in controlling plasma HDL in humans, SR-BI may influence the development and progression of atherosclerosis and may be an attractive candidate for therapeutic intervention in this disease.