Proprotein Convertase Subtilisin/Kexin Type 9 Interacts With Apolipoprotein B and Prevents Its Intracellular Degradation, Irrespective of the Low-Density Lipoprotein Receptor

Abstract

Objective-Proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulates the low-density lipoprotein (LDL) receptor (LDLR) in hepatocytes and therefore plays an important role in controlling circulating levels of LDL-cholesterol. To date, the relationship between PCSK9 and metabolism of apolipoprotein B (apoB), the structural protein of LDL, has been controversial and remains to be clarified. Methods and Results-We assessed the impact of PCSK9 overexpression (≈400-fold above baseline) on apoB synthesis and secretion in 3 mouse models: wild-type C57BL/6 mice and LDLR-null mice (Ldlr −/− and Ldlr). Irrespective of LDLR expression, mice transduced with the PCSK9 gene invariably exhibited increased levels of plasma cholesterol, triacylglycerol, and apoB. Consistent with these findings, the levels of very-low-density lipoprotein and LDL were also increased whereas high-density lipoprotein levels were unchanged. Importantly, we demonstrated that endogenous PCSK9 interacted with apoB in hepatocytes. The PCSK9/apoB interaction resulted in increased production of apoB, possibly through the inhibition of intracellular apoB degradation via the autophagosome/lysosome pathway. Conclusion-We propose a new role for PCSK9 that involves shuttling between apoB and LDLR. The present study thus provides new insights into the action of PCSK9 in regulating apoB metabolism.

Experimental and clinical pharmacology: PCSK9 inhibitors - mechanisms of action

“…7,8 However, this finding is inconsistent with that in humans with LDL-receptor-negative familial hypercholesterolaemia, in whom blocking the action of PCSK9 does not decrease plasma concentrations of LDL cholesterol. 9 Animal studies have suggested roles for PCSK9 in non-hepatic tissue.…”

Lipoprotein(a) and inhibitors of proprotein convertase subtilisin/kexin type 9

“…Although the effects of PCSK9 on SR-B1 have yet to be clarified, PCSK9 facilitates the atherosclerotic process under conditions of high blood levels of LDL with oxidized LDL; therefore, an increase (removal) in the SR-B1 expression by PCSK9 inhibitors may result in Lp(a) reduction via the SR-B1 pathway. Independent of the LDL receptor, we should also consider the influence of apoB-100 synthesis/availability on the association of Lp(a) with PCSK9 (29,30). A study in mice investigated the effects of PCSK9 on apoB synthesis (30).…”

PCSK9: A key factor modulating atherosclerosis

“…Many potential injurious agents, including hemodynamic and biochemical factors, such as smoking, chronic hyperlipidemia, hypertension, hyperglycemia, infections, and immunological injury, lead to alterations in attachments between endothelial cells or those between endothelial cells and connective tissue 17) . This situation permits hemodynamic forces caused by the blood flow shear to increase and possibly cause focal endothelial desquamation, which is followed by the adhe-ous investigations involving cells, mice, and humans have suggested that PCSK9 may play a role in regulating apoB synthesis and secretion, and they have provided convincing evidence of a direct endogenous protein-protein interaction between PCSK9 and apoB 25) . Moreover, GOF forms of PCSK9, such as D374Y and S127R, have higher binding affinities for apoB than wild-type PCSK9 [25][26][27] .…”

“…This situation permits hemodynamic forces caused by the blood flow shear to increase and possibly cause focal endothelial desquamation, which is followed by the adhe-ous investigations involving cells, mice, and humans have suggested that PCSK9 may play a role in regulating apoB synthesis and secretion, and they have provided convincing evidence of a direct endogenous protein-protein interaction between PCSK9 and apoB 25) . Moreover, GOF forms of PCSK9, such as D374Y and S127R, have higher binding affinities for apoB than wild-type PCSK9 [25][26][27] . The PCSK9/apoB interaction inhibits the intracellular degradation of apoB, regardless of LDLR, which results in the increased secretion of apoB and apoB-containing lipoproteins.…”