Proprotein convertase subtilisin/kexin type 9 (PCSK9) may increase the release of lipoprotein(a) by liver cells, and treatment with a PCSK9 inhibitor may reduce the secretion of lipoprotein(a) by liver cells, according to a study published Oct. 31 in JACC: Basic to Translational Science.

In order to understand how, unlike statins, PCSK9 inhibitors reduce the circulating levels of lipoprotein(a) in patients, Elise F. Villard, PhD, and colleagues investigated the role of PCSK9 and of the low-density lipoprotein (LDL) receptor in mediating lipoprotein(a) cellular uptake.

The researchers looked at skin cells from patients with and without familial hypercholesterolemia as well as cultures from liver cells. Results showed that lipoprotein(a) cellular uptake occurred in a LDL receptor-independent manner. Neither PCSK9 nor alirocumab altered the internalization of lipoprotein(a). However, the secretion of apolipoprotein(a) in liver cells sharply increased when treated with PCSK9, but treatment with alirocumab reversed this effect.

“This study raises the optimistic note that further dissection of the molecular mechanisms by which PCSK9 modulates lipoprotein(a) production will not only increase our understanding of the effects of this pleiotropic molecule but also provide potential new areas of development for therapies that can modulate lipoprotein(a),” said Peter Libby, MD, FACC, in an editorial comment.

“Given the dearth of acceptable pharmacological approaches to lowering lipoprotein(a) in our current armamentarium, the advent of the anti-PCSK9 antibodies and the new insight that they lower lipoprotein(a) plasma concentrations by inhibiting hepatic production rather than by augmenting catabolism, as they do in the case of LDL, has both mechanistic and therapeutic implications for the future,” he adds.

Keywords: Antibodies, Monoclonal, Apolipoproteins A, Apoprotein(a), Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Lipoprotein(a), Lipoproteins, LDL, Liver, Proprotein Convertases, Receptors, LDL, Subtilisins

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