Lipoprotein Markers of Cardiovascular Risk in Metabolic Conditions and the Impact of Interventions

Abstract

Atherogenic modification of low-density lipoprotein (LDL) and impaired high-density lipoprotein (HDL) functionality are key contributors to atherosclerosis and cardiovascular disease (CVD). Markers of LDL modification and HDL functionality are therefore important biomarkers of CVD risk that could help provide insights into the underlying pathophysiology and the impact of risk modification therapies. Oxidative modification of LDL results in generation of various oxidation specific epitopes, including oxidised phospholipids (OxPL) which are preferentially bound to lipoprotein(a) [Lp(a)] in circulation. OxPL measured on apolipoprotein B-100 (OxPL-apoB) is closely associated with Lp(a) and both are independent predictors for CVD. HDL has multiple atheroprotective functions including cholesterol efflux capacity, and more recently, it has emerged as a transporter of micro-ribonucleic acids (miRNA) which have been shown to confer some of the protective effects of HDL. This thesis examined these lipoprotein markers of CVD risk in obesity and the changes that occur after bariatric surgery, as well as in polycystic ovarian syndrome (PCOS) with specific focus on the impact of insulin resistance. The effects of extended release niacin and laropiprant (ERN/LRP) added to statin therapy on levels of OxPL-apoB and Lp(a) were also assessed. Studies in this thesis demonstrated a divergence in OxPL-apoB and Lp(a) following bariatric surgery which was not previously reported. The decrease in OxPL-apoB reflect an overall reduction in oxidative stress while the increase in Lp(a) was postulated to relate to improvement in hepatic steatosis and function resulting in increased hepatic synthesis. Expression of specific HDL-associated miRNAs were increased after bariatric surgery, in association with improvements in other markers of HDL functionality, indicating an overall improvement in HDL function. Insulin resistance was shown to be a key factor underlying the CVD risk associated with PCOS, which was reflected by impairment in HDL functionality and markers of oxidative modification and glycation of LDL. Levels of OxPL-apoB and Lp(a) can be impacted by lipid-modifying therapies, and reduction in Lp(a) but not OxPL-apoB was observed with ERN/LRP when added to statin therapy.

Date of Award	22 Mar 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Handrean Soran (Main Supervisor), Rachelle Donn (Co Supervisor) & Rayaz Malik (Co Supervisor)