Date of Award
Level of Access
Doctor of Philosophy (PhD)
Second Committee Member
Carol H. Kim
Third Committee Member
Karen L. Svenson
The proprotein convertase subtilisin/kexin (PCSK) is a serine endopeptidase family. PCSKs cleave amino acid residues and modulate the activity of precursor proteins. Evidence from patients and animal models carrying genetic alterations in PCSKs show that they are involved in various metabolic processes. These studies further revealed the molecular mechanism by which genetic alterations of some PCSKs impair normal molecular and physiological functions, which in turn lead to cardiovascular disease (CVD). Several PCSKs are implicated in high-derisity lipoprotein (HDL) metabolism. HDL is an independent risk factor for CVD and a lower HDL level is correlated with higher CVD risk. HDL not only removes excessive amount of cholesterol from blood and peripheral tissues, but also inhibits pro-atherogenic processes including inflammation, oxidation, and thrombosis.
PCSK3, PCSK5, and PCSK6 process two triglyceride lipase family members, endothelial lipase and lipoprotein lipase, which are important for HDL remodeling. Recent HDL quantitative locus analyses in our laboratory suggested that two other PCSKs, PCSK1 and PCSK9, may also be involved in HDL metabolism.
During my PhD training, I focused on validating the role for PCSK1 and PCSK9 in HDL metabolism using mouse models and further revealed their molecular mechanisms. Chapter 1 summarizes the role and action of five PCSKs (PCSK1, 3, 5, 6, and 9) in HDL metabolism and presents an integrative model in which PCSKs may indirectly influence HDL metabolism through other metabolic processes: non-HDL cholesterol, lipid, insulin, glucose and bile acid metabolism. Chapter 2 demonstrates that PCSK9 controls circulating HDL cholesterol concentration by regulating the level of apolipoprotein E (APOE)-containing HDL subfractions via the low-density lipoprotein receptor (LDLR). Chapter 3 demonstrates that PCSK1 controls lipid-free APOA1 level in serum by regulating the activity of phospholipid transfer protein (PLTP).
My PhD dissertation work increases the knowledge of the role of PCSKs in HDL metabolism and also provides an integrative point of view for molecular networking between the five PCSKs in complex metabolic processes. A greater understanding of the molecular and physiological functions of PCSKs will improve therapeutic strategies and drug efficacy for CVD, with fewer adverse effects.
Choi, Seungbum, "Role of Proprotein Convertases in HDL Metabolism" (2013). Electronic Theses and Dissertations. 2066.