Stulnig T M, Klocker H, Harwood H J, Jürgens G, Schönitzer D, Jarosch E, Huber L A, Amberger A, Wick G
Institute for General and Experimental Pathology, University of Innsbruck, Austria.
Arterioscler Thromb Vasc Biol. 1995 Jul;15(7):872-8. doi: 10.1161/01.atv.15.7.872.
The LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase play primary roles in the regulation of cellular cholesterol metabolism. To investigate the transcriptional regulation of lipid metabolism under physiological conditions ex vivo and its alterations during aging, we analyzed both the activity and mRNA concentration of the LDL receptor and HMG-CoA reductase in freshly isolated lymphocytes from healthy young and elderly donors. Data from fluorescent reverse transcriptase-polymerase chain reaction indicated that not only plasma LDL but also plasma HDL downregulates lymphocyte LDL receptor mRNA. Downregulation by HDL was three times more effective than that by LDL and presumably involved specific HDL binding sites. There was coordinate regulation of HMG-CoA reductase mRNA with LDL receptor mRNA that was independent of plasma lipoprotein concentrations. Despite elevated plasma concentrations of LDL, lymphocytes from elderly donors paradoxically expressed increased levels of the LDL receptor (P = .030) and HMG-CoA reductase mRNA (P = .062). The age-related dysregulation of the LDL receptor was predominantly due to impaired downregulation by plasma LDL rather than by HDL. Thus, not only LDL but also HDL and age significantly influences the transcriptional regulation of the LDL receptor in extrahepatic cells in vivo.
低密度脂蛋白受体和3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶在细胞胆固醇代谢调节中起主要作用。为了研究离体生理条件下脂质代谢的转录调控及其在衰老过程中的变化，我们分析了从健康年轻和老年供体新鲜分离的淋巴细胞中低密度脂蛋白受体和HMG-CoA还原酶的活性及mRNA浓度。荧光逆转录聚合酶链反应的数据表明，不仅血浆低密度脂蛋白，而且血浆高密度脂蛋白均可下调淋巴细胞低密度脂蛋白受体mRNA。高密度脂蛋白的下调作用比低密度脂蛋白强三倍，可能涉及特定的高密度脂蛋白结合位点。HMG-CoA还原酶mRNA与低密度脂蛋白受体mRNA存在协同调节，且与血浆脂蛋白浓度无关。尽管老年供体的血浆低密度脂蛋白浓度升高，但令人惊讶的是，其淋巴细胞中低密度脂蛋白受体（P = 0.030）和HMG-CoA还原酶mRNA（P = 0.062）的表达水平却升高。与年龄相关的低密度脂蛋白受体失调主要是由于血浆低密度脂蛋白而非高密度脂蛋白的下调受损。因此，不仅低密度脂蛋白，而且高密度脂蛋白和年龄均会在体内显著影响肝外细胞中低密度脂蛋白受体的转录调控。
