Abstract 18351: Proprotein Convertase Subtilisin/kexin Type 9 Interacts and Regulates ApolipoproteinB
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in LDL metabolism. It acts as a chaperon that binds the LDL receptor (LDLR), targeting it for degradation, thus increases LDL levels indirectly. The role of PCSK9 in apolipoprotein B (apoB) regulation, the main structure protein of VLDL and LDL particles, remains controversial. We hypothesizes that PCSK9 interacts with apoB and regulates apoB production. Here we present overexpression of PCSK9 in mice increases VLDL and LDL cholesterol levels and apoB production. Moreover, we demonstrated a direct interaction between PCSK9 and truncated apoB proteins.
Methods and Results: We transduced E2b-deleted adenovirus expressing PCSK9 (ΔE2b-AdPCSK9) (5×1010 virus particles/mouse) to Ldlr-/-, LDb (Ldlr-/-Apobec1-/-), and C57BL/6 wildtype mice. Over-expressing PCSK9 in these mice increased the cholesterol levels of VLDL and LDL, and apoB levels markedly. PCSK9 was associated mainly with VLDL and LDL particles. Using co-immunoprecipitation method, we demonstrated that PCSK9 co-immunoprecipitated with truncated apoB of apoB48 and apoB18. We performed pulse-chase experiment of apoB in primary hepatocytes isolated from LDb mice transduced with ΔE2b-PCSK9, and we showed that over-expressing PCSK9 increased the synthesis and secretion of apoB more than 5-fold in comparison with hepatocytes transcuced with ΔE2b-AdNull. We are in the process of elucidation the role of PCSK9 that inhibits the degradation of apoB intracellularly.
Conclusions: Our results demonstrated that PCSK9 interacted with apoB and regulated apoB production, which suggests the second function of PCSK9 as a chaperon molecule. In the cell, PCSK9 interacted with apoB to inhibit apoB degradation, resulting in increase apoB secretion. In the circulation, PCSK9 interacts with LDL receptor to block the uptake of LDL. Both processes lead to the increase of LDL levels and the consequence of hyperlipidemia. Thus, the delineation of PCSK9 function would allow us to develop the best suitable therapeutic strategies to regulate PCSK9 for the treatment of hyperlipidemia and the prevention of coronary artery disease.
- © 2010 by American Heart Association, Inc.