CHANGES IN HIGH-DENSITY LIPOPROTEIN FUNCTIONALITY, LIPOPROTEINS METABOLISM AND CARDIOVASCULAR DISEASE BIOMARKERS FOLLOWING PHARMACOLOGICAL INTERVENTIONS AND BARIATRIC SURGERY-INDUCED WEIGHT LOSS

Abstract

Abstract Background: Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Obesity-related systemic inflammation and derangements in lipoproteins metabolism, quality and functionality are important risk factors for cardiovascular diseases in obese individuals and diabetes. It is important to assess qualitative changes in lipoproteins and changes in high density lipoprotein (HDL) functionality in obese patients to realise the exact nature of derangements in lipoproteins metabolism. Standard lipid profile test used routinely in clinical practice fails to detect these important derangements. In obesity and diabetes HDL`s capacity to promote cholesterol efflux and reverse cholesterol transport is compromised. Many other aspects of HDL functionality are also impaired. It is important to assess and understand the impact of weight loss and pharmacological interventions on systemic inflammation, lipoproteins metabolism and quality as well as HDL`s functions. Aim: Investigate improvement in HDL metabolism and functionality, lipoprotein (a) (Lp(a)), oxidised phospholipid on apolipoproteins B (ox-PL-apoB), glycaemia, systemic and vascular inflammation markers following bariatric surgery-induced weight loss and extended-release niacin/laropiprant (ERN/LRPT) and atorvastatin (high and low dose) treatments. Method: This thesis is composed of three clinical studies. In the first study, the effect of bariatric surgery-induced weight loss on systemic inflammation, HDL functions, lipoproteins, Lp(a) and ox-PL-apoB was studied. Patients before and after bariatric surgery were assessed. The second study was a randomised controlled double-blind cross-over trial of ERN/LRPT of 38 hyperlipidemic statin-treated patients, the effect of ERN/LRPT on HDL functions, Lp(a) and ox-PL-apoB were assessed. In the third study, the effect of high and low dose atorvastatin on cholesterol efflux capacity (CEC) and serum amyloid A were studied in 119 diabetic patients in a randomised double-blind study. Patients were randomised to receive low dose atorvastatin 10mg (N=59) or high dose atorvastatin 80mg (N=60) daily, the effect of atorvastatin after 12 months of randomisation were assessed. Results: Cholesterol efflux capacity, HDL-C, Lp(a) and serum paraoxonase1 activity increased significantly after bariatric surgery-induced weight loss. Serum triglyceride, myeloperoxidase mass, myeloperoxidase peroxidation activity, serum amyloid A, anti-apoA-I antibodies, Ox-PL-apoB, tumor necrosis factor alpha, interleukin 6, high-sensitivity C-reactive protein, resistin, monocyte-chemotactic protein 1, Inter cellular adhesion molecule 1, E-selectin, weight, body mass index, waist circumference, HbA1c, insulin and homeostasis model assessment of insulin resistance decreased significantly following surgery. However total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) did not change significantly. ERN/LRPT increased cholesterol efflux capacity and HDL-C significantly compared to placebo. Furthermore, serum triglyceride, TC, LDL-C, Lp(a), Serum amyloid A, apoB and cholesteryl ester transfer protein activity were reduced significantly following treatment. Comparing high to low dose atorvastatin, at one year following treatment, triglyceride, TC, LDL-C and apoB were significantly lower in high dose group than low dose group. However CEC and HDL-C did not change significantly. Conclusions: HDL functionality markers and its capacity to promote cholesterol efflux improved significantly following bariatric surgery-induced weight loss. HDL-C increased and CEC capacity improved modestly after ERN/LRPT treatment. Glucose metabolism and systemic and vascular inflammation biomarkers all improved significantly after surgery. High dose atorvastatin lowered atherogenic lipoproteins more than the low dose. However, atorvastatin had no effect on HDL-C, CEC or markers of HDL functionality.

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Anthony Heagerty (Supervisor) & Handrean Soran (Supervisor)