Vanderbilt University, Cardiovascular Medicine, Nashville, TN 37232-6300, USA.
Circulation. 2013 Jun 18;127(24):2403-13. doi: 10.1161/CIRCULATIONAHA.113.001592. Epub 2013 May 20.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates low-density lipoprotein (LDL) receptor (LDLR) degradation, thus influencing serum cholesterol levels. However, dysfunctional LDLR causes hypercholesterolemia without affecting PCSK9 clearance from the circulation.
To study the reciprocal effects of PCSK9 and LDLR and the resultant effects on serum cholesterol, we produced transgenic mice expressing human (h) PCSK9. Although hPCSK9 was expressed mainly in the kidney, LDLR degradation was more evident in the liver. Adrenal LDLR levels were not affected, likely because of the impaired PCSK9 retention in this tissue. In addition, hPCSK9 expression increased hepatic secretion of apolipoprotein B-containing lipoproteins in an LDLR-independent fashion. Expression of hPCSK9 raised serum murine PCSK9 levels by 4.3-fold in wild-type mice and not at all in LDLR(-/-) mice, in which murine PCSK9 levels were already 10-fold higher than in wild-type mice. In addition, LDLR(+/-) mice had a 2.7-fold elevation in murine PCSK9 levels and no elevation in cholesterol levels. Conversely, acute expression of human LDLR in transgenic mice caused a 70% decrease in serum murine PCSK9 levels. Turnover studies using physiological levels of hPCSK9 showed rapid clearance in wild-type mice (half-life, 5.2 minutes), faster clearance in human LDLR transgenics (2.9 minutes), and much slower clearance in LDLR(-/-) recipients (50.5 minutes). Supportive results were obtained with an in vitro system. Finally, up to 30% of serum hPCSK9 was associated with LDL regardless of LDLR expression.
Our results support a scenario in which LDLR represents the main route of elimination of PCSK9 and a reciprocal regulation between these 2 proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels.
前蛋白转化酶枯草溶菌素 9（PCSK9）调节低密度脂蛋白（LDL）受体（LDLR）降解，从而影响血清胆固醇水平。然而，LDLR 功能障碍会导致高胆固醇血症，而不会影响 PCSK9 从循环中清除。
为了研究 PCSK9 和 LDLR 的相互作用及其对血清胆固醇的影响，我们制备了表达人（h）PCSK9 的转基因小鼠。尽管 hPCSK9 主要在肾脏中表达，但 LDLR 的降解在肝脏中更为明显。肾上腺 LDLR 水平不受影响，可能是由于该组织中 PCSK9 的保留受损。此外，hPCSK9 的表达以 LDLR 不依赖的方式增加了载脂蛋白 B 含有脂蛋白的肝分泌。在野生型小鼠中，hPCSK9 的表达使血清中鼠 PCSK9 水平升高了 4.3 倍，而在 LDLR（-/-）小鼠中则没有升高，LDLR（-/-）小鼠中的鼠 PCSK9 水平已经比野生型小鼠高 10 倍。此外，LDLR（+/-）小鼠中的鼠 PCSK9 水平升高了 2.7 倍，而胆固醇水平没有升高。相反，在转基因小鼠中急性表达人 LDLR 导致血清中鼠 PCSK9 水平降低了 70%。使用生理水平的 hPCSK9 进行的周转率研究表明，在野生型小鼠中清除速度很快（半衰期为 5.2 分钟），在人 LDLR 转基因小鼠中清除速度更快（2.9 分钟），而在 LDLR（-/-）受体中清除速度更慢（50.5 分钟）。在体外系统中得到了支持性结果。最后，无论 LDLR 的表达如何，高达 30%的血清 hPCSK9 与 LDL 相关。
我们的结果支持这样一种情况，即 LDLR 是 PCSK9 的主要消除途径，这两种蛋白质之间的相互调节控制着血清 PCSK9 水平、肝 LDLR 表达和血清 LDL 水平。
