Abstract 123: Reciprocal Regulation of Plasma PCSK9 and Cell-surface Low-density Lipoprotein Receptor
Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates low-density lipoprotein (LDL) receptor (LDLR) degradation, thus influencing serum cholesterol levels. On the other hand, LDLR binds to and clears PCSK9 from the circulation, thus modulating its serum levels. To study the global and reciprocal effects of PCSK9 and LDLR on serum cholesterol, we developed transgenic mice expressing human (h) PCSK9 and characterized its activity, serum levels, and tissue distribution. Serum hPCSK9 concentration in transgenic mice was 2181±423 ng/ml, about 10 times higher than normal level in human serum. Although hPCSK9 was expressed mainly in the kidney, LDLR degradation activity was most evident in the liver and small intestine. In contrast, LDLR levels were not affected by hPCSK9 expression in the adrenals and large intestine. On a chow diet, hPCSK9 transgenic mice on either C57BL/6 (wild-type, WT) or LDLR-/- background had higher cholesterol levels than their non-transgenic counterparts. Human PCSK9 transgenic mice had over a 4-fold increase in murine (m) PCSK9 serum levels compared to WT controls. However, transgenic expression of hPCSK9 in LDLR-/- mice did not affect the already elevated levels of mPCSK9. On the other hand, induction of hLDLR expression in transgenic mice caused a dramatic decrease in mPCSK9 levels. In addition hPCSK9 levels were increased by 2 fold in transgenic mice under LDLR-/- compare to WT background. Turnover studies with native PCSK9 showed rapid serum clearance in WT mice (half-life 5.2 min), whereas clearance was much slower in LDLR-/- recipient mice (50.5 min), and faster in hLDLR transgenic mice (2.9 min). In WT mice the injected PCSK9 accumulated in the liver and kidney but not in the adrenal gland. Ultracentrifugation and FLPC analysis showed that approximately one quarter of circulating hPCSK9 is associated with LDL, and that the LDL-associated PCSK9 is mainly in monomeric form. Our results show a reciprocal regulation between LDLR and PCSK9, which determines serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels. Understanding these interactions will increase our knowledge of serum cholesterol homeostasis and should provide the basis for an intelligent design of anti-PCSK9 therapies.
- © 2013 by American Heart Association, Inc.