Serum PCSK9 and Cell Surface Low-Density Lipoprotein Receptor: Evidence for a Reciprocal Regulation
Background—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.
Methods and Results—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 mainly expressed in the kidney, LDLR degradation was more evident in the liver. Adrenal LDLR levels were not affected, likely due to impaired PCSK9 retention in this tissue. In addition, hPCSK9 expression increased hepatic secretion of apoB-containing lipoproteins in an LDLR-independent fashion. Expression of hPCSK9 raised serum murine (m) PCSK9 levels by 4.3-fold in wild-type (WT) mice and not at all in LDLR-/- mice, where mPCSK9 levels were already 10-fold higher than in WT mice. In addition, LDLR+/- mice had 2.7-fold elevation in mPCSK9 levels and no elevation in cholesterol levels. Conversely, acute expression of hLDLR in transgenic mice caused a 70% decrease in serum mPCSK9 levels. Turnover studies using physiological levels of hPCSK9 showed rapid clearance in WT (half-life 5.2_min), faster in hLDLR transgenics (2.9_min), and much slower in LDLR-/- recipients (50.5_min). Supportive results were obtained using an in vitro system. Finally, up to 30% of serum hPCSK9 was associated with LDL regardless of LDLR expression.
Conclusions—Our results support a scenario where LDLR represents the main route of elimination of PCSK9, and a reciprocal regulation between these two proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels.
- Received March 21, 2013.
- Accepted April 23, 2013.