Date of Award

7-25-2018

Publication Type

Master Thesis

Degree Name

M.Sc.

Department

Chemistry and Biochemistry

Keywords

Apolipoprotein(a), Lipoprotein(a), Sortilin

Supervisor

Koschinsky, Marlys

Supervisor

Boffa, Michael

Rights

info:eu-repo/semantics/openAccess

Abstract

Elevated levels of lipoprotein(a) (Lp(a)) are an independent, causal risk factor for coronary heart disease. Lp(a) is structurally similar to low-density lipoprotein (LDL), but is distinguished by the covalent addition of apolipoprotein(a) (apo(a)), which is a polymorphic glycoprotein that shares homology with plasminogen. Genomewide association studies (GWAS) identified that mutations in the vicinity of the SORT1 gene are associated with a ~5.8 mg/dL decrease in LDL cholesterol, 18% decrease in coronary artery disease risk, and 40% decrease myocardial infarction risk. Sortilin, the protein product of SORT1, was found to directly associate with apoB-100, and regulate apoB-100/VLDL secretion and LDL catabolism. The work in this thesis evaluates if sortilin plays a similar role in regulating Lp(a)/apo(a) metabolism. Pulse-chase analysis demonstrated that sortilin overexpression increased the accumulation of intracellular and secreted apo(a); the opposite effect was observed with reduced sortilin expression. Critical roles in mediating the ability of sortilin to increase apo(a) secretion were identified for the weak lysine bindings sites (LBS) in kringle IV type 7 and type 8, but not the strong LBS in kringle IV type 10, of apo(a). Sortilin overexpression also increased Lp(a) internalization, with data suggesting that this pathway occurs independently of the LDL receptor. Treatment with a lysine analog abolished the ability of sortilin to increase Lp(a) internalization. The effects of sortilin overexpression on both apo(a) secretion and Lp(a) catabolism were dependent upon the ability of sortilin to act as a trafficking receptor. Naturally occurring polymorphisms of sortilin were found to be expressed in individuals with elevated levels of Lp(a). Expression of these sortilin mutants resulted in altered apo(a) secretion and Lp(a) internalization compared to wild-type sortilin. Taken together, our data suggest that sortilin is involved in the regulation of Lp(a)/apo(a) metabolism.

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