What is the clinical evidence from this study?

Study design: Other. Population: Elevated Lipoprotein(a). Intervention: PCSK9 vs. No PCSK9. Primary outcome: Lp(a) and apo(a) internalization.

July 27, 2017Open Access

Roles of the low density lipoprotein receptor and related receptors in inhibition of lipoprotein(a) internalization by proprotein convertase subtilisin/kexin type 9

RRRocco RomagnuoloUniversity Health Network CSCorey A. ScipioneUniversity Health Network SMSantica M. MarcovinaPreventive Cardiology

Key Result

PCSK9 decreased Lp(a) and apo(a) internalization by human hepatoma cells and primary hepatocytes through an LDLR-dependent mechanism, while VLDLR, LRP-8, and LRP-1 did not play a role.

Structured PICO

Population

Hepatic cells including Huh7 human hepatoma cells, primary mouse and human hepatocytes, HepG2 cells, and LDLR-deficient mouse hepatocytes

Intervention

PCSK9 (wild-type, gain-of-function, and loss-of-function variants) and overexpression of human LDLR

Comparator

Control conditions (absence of PCSK9, wild-type vs mutants, LDLR-deficient vs overexpressed)

Outcome

Lp(a) and/or apo(a) internalizationsurrogate

This preclinical study demonstrates that PCSK9 inhibits Lp(a) clearance primarily through the low-density lipoprotein receptor (LDLR), providing a mechanistic basis for the Lp(a)-lowering effects of PCSK9 inhibitors.

Limitations

High non-specific binding of Lp(a) to collagen matrix in primary human hepatocytes
In vitro findings may not fully reflect in vivo physiological mechanisms of Lp(a) clearance

Abstract

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for cardiovascular disease. The mechanisms underlying Lp(a) clearance from plasma remain unclear, which is an obvious barrier to the development of therapies to specifically lower levels of this lipoprotein. Recently, it has been documented that monoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) can lower plasma Lp(a) levels by 30%. Since PCSK9 acts primarily through the low density lipoprotein receptor (LDLR), this result is in conflict with the prevailing view that the LDLR does not participate in Lp(a) clearance. To support our recent findings in HepG2 cells that the LDLR can act as a bona fide receptor for Lp(a) whose effects are sensitive to PCSK9, we undertook a series of Lp(a) internalization experiments using different hepatic cells, with different variants of PCSK9, and with different members of the LDLR family. We found that PCSK9 decreased Lp(a) and/or apo(a) internalization by Huh7 human hepatoma cells and by primary mouse and human hepatocytes. Overexpression of human LDLR appeared to enhance apo(a)/Lp(a) internalization in both types of primary cells. Importantly, internalization of Lp(a) by LDLR-deficient mouse hepatocytes was not affected by PCSK9, but the effect of PCSK9 was restored upon overexpression of human LDLR. In HepG2 cells, Lp(a) internalization was decreased by gain-of-function mutants of PCSK9 more than by wild-type PCSK9, and a loss-of function variant had a reduced ability to influence Lp(a) internalization. Apo(a) internalization by HepG2 cells was not affected by apo(a) isoform size. Finally, we showed that very low density lipoprotein receptor (VLDLR), LDR-related protein (LRP)-8, and LRP-1 do not play a role in Lp(a) internalization or the effect of PCSK9 on Lp(a) internalization. Our findings are consistent with the idea that PCSK9 inhibits Lp(a) clearance through the LDLR, but do not exclude other effects of PCSK9 such as on Lp(a) biosynthesis.

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