Electronic Thesis and Dissertation Repository

Apolipoprotein(a) Secretion is Modulated by Sortilin, Proprotein Convertase Subtilisin/Kexin Type 9, and Microsomal Triglyceride Transfer Protein

Justin Clark, The University of Western Ontario

Abstract

Elevated plasma lipoprotein(a) (Lp(a)) levels are a causal risk factor for cardiovascular disease (CVD), but development of specific Lp(a) lowering therapeutics has been hindered by insufficient understanding of Lp(a) biology. For example, the location of the noncovalent interaction that precedes the extracellular disulfide linkage between apolipoprotein(a) (apo(a)) and apolipoprotein B-100 (apoB-100) in Lp(a) biosynthesis is unclear. In this study we modulated known intracellular regulators of apoB-100 production and then assessed apo(a) secretion from human HepG2 cells expressing 17-kringle (17K) apo(a) isoform variants using pulse-chase analysis. Treating 17K-expressing HepG2 cells withproprotein convertase subtilisin-kexin type 9(PCSK9) significantly increased apo(a) secretion. Treating the same cell line with Lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, significantly decreased apo(a) secretion. Overexpression of human sortilin variants (F404Y and K302E) significantly increased apo(a) secretion relative to wild-type. Our findings suggest a role for sortilin, PCSK9, and MTP in modulating Lp(a) levels through effects on apo(a) secretion, possibly through impacting the intracellular bioavailability of apoB-100.