Liver is the primary organ for clearance of triglyceride-rich remnant lipoproteins (TRL) via LDL receptor (LDLR), ), LDLR-related protein-1 (LRP1) and syndecan-1. Elevated plasma TRL due to reduced liver clearance is a major cause of dyslipidemia, cardiovascular disease and mortality in chronic kidney disease (CKD). Although substantial effort has been put into understanding the molecular mechanisms underlying dyslipidemia in CKD and development of novel therapies, dyslipidemia related to CKD still remains a huge challenge. Recently, heparan sulfate proteoglycans (HSPG) has been reported to facilitate LDLR degradation by proprotein convertase subtilisin kexin type-9 (PCSK9). In this thesis, we have investigated i) the effects of CKD on primary hepatic lipoprotein receptors (LDLR, LRP1 and syndecan-1); ii) the interaction of PCSK9 and hepatic HSPGs in connection to plasma lipids and iii) whether lipid lowering therapies are associated with reductions in plasma PCSK9 and syndecan-1 and clinical outcomes. The studies reported in this thesis provide novel insights into the mechanisms underlying dyslipidemia in renal diseases that involve increased hepatic HSPG interaction with PCSK9 leading to reduced clearance of TRL. At present, where current cholesterol-lowering strategies to treat dyslipidemia in CKD are still insufficient, studies present in this thesis suggest that PCSK9 inhibition can be beneficial in improving lipid levels in CKD. Further, our study opens new venues for future development of cost-effective heparin mimetics as PCSK9 inhibitors.
|Kwalificatie||Doctor of Philosophy|
|Datum van toekenning||2-mrt.-2022|
|Plaats van publicatie||[Groningen]|
|Status||Published - 2022|