Rigotti A, Trigatti B L, Penman M, Rayburn H, Herz J, Krieger M
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12610-5. doi: 10.1073/pnas.94.23.12610.
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 approximately 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.
血浆高密度脂蛋白（HDL）具有抗动脉粥样硬化作用，被认为可从外周组织清除胆固醇，并通过选择性摄取途径将胆固醇酯输送至肝脏（逆向胆固醇转运）和类固醇生成组织（如肾上腺用于储存和激素合成）。尽管HDL在生理和病理生理方面具有重要意义，但其细胞代谢尚未得到很好的界定。B类I型清道夫受体（SR-BI）被认为在HDL代谢中起重要作用，原因如下：（i）它是一种细胞表面HDL受体，可介导培养细胞中的选择性胆固醇摄取；（ii）其受生理调节的表达在肝脏和类固醇生成组织中最为丰富；（iii）肝脏中过表达会显著降低血浆HDL水平。为了直接测试SR-BI在HDL代谢中的正常作用，我们构建了SR-BI基因靶向敲除突变小鼠。与野生型对照相比，杂合子和纯合子突变体的血浆胆固醇浓度分别升高了约31%和125%，这是由于形成了大的、含载脂蛋白A-I（apoA-I）的颗粒，而肾上腺胆固醇含量分别降低了42%和72%。HDL中的主要蛋白质apoA-I的血浆浓度在突变体中未发生变化。这与脂蛋白大小增加相结合，表明突变体中血浆胆固醇升高是由于选择性胆固醇摄取减少所致。这些结果为以下观点提供了有力支持：在小鼠中，编码SR-BI的基因在决定血浆脂蛋白胆固醇（主要是HDL）水平和肾上腺胆固醇储存积累方面起关键作用。如果SR-BI在控制人类血浆HDL方面具有类似作用，它可能会影响动脉粥样硬化的发生和发展，并且可能是这种疾病治疗干预的一个有吸引力的候选靶点。
