Pharmacological Modulation of Lipoprotein Metabolism

Gaw, Allan (1992) Pharmacological Modulation of Lipoprotein Metabolism. PhD thesis, University of Glasgow.

Abstract

This thesis has two inter-related aims: to investigate the effects of a series of lipid lowering regimens on the metabolism of the apoB containing lipoproteins and to provide new information on the pathophysiology of human lipoprotein metabolism. By studying the effects of simvastatin, the resins colestipol and cholestyramine, acipimox and the fibric acid derivatives ciprofibrate and fenofibrate, alone and in selected combinations, it was possible to offer new mechanisms of action for these lipid lowering drugs in patients with primary moderate hypercholesterolaemia. The studies involved the measurement of lipids, lipoproteins and an assessment of either apoB or apo-LDL metabolism at baseline and during the drug therapies. The data obtained from the kinetic studies were analysed using a multicompartmental mathematical modelling strategy. This allowed the computation of rate constants and sub-compartmental masses for each of the apoB containing lipoproteins, which served as a mathematical approximation of apoB or apo-LDL metabolism. Additionally, in the case of simvastatin and fenofibrate, an assessment of the in vivo effects of these drugs on cholesterol biosynthesis was made using assays for the cholesterol precursors, mevalonic acid and lathosterol. The main findings from these studies were a new appreciation for the metabolic heterogeneity that underlies primary moderate hypercholesterolaemia, an increased recognition of the role of the apoB/E receptor in the clearance of LDL precursors as seen in studies with simvastatin and colestipol, formulation of a proposed mechanism for the hypertriglyceridaemia often noted with sequestrant resin therapy and support for the significance of hepatic lipase in IDL-LDL conversion as demonstrated in the study with acipimox. Confirmation of the efficacy of combined lipid lowering therapy is offered, as is a novel mechanism for the enhanced LDL clearance observed with fibrate therapy. The latter involves drug induced changes in the ligand rather than the receptor. Further investigation of the effects of fenofibrate suggested that, unlike simvastatin, this fibrate had no consistent effect on cholesterol biosynthesis. The latter is an important new in vivo observation which supports a growing body of in vitro work. This thesis concludes with a discussion of unanswered questions which are of interest both in terms of lipoprotein metabolism and the development of atherosclerosis. New approaches to the study of lipoprotein kinetics are suggested involving the application of stable isotope technology , and an hypothesis, based on kinetic and structural observations, that the direct synthesis of LDL apoB is linked more closely with the larger, lighter LDL subfractions, is stated.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: John Shepard
• Keywords: Medicine, Pharmacology
• Date of Award: 1992
• Depositing User: Enlighten Team
• Unique ID: glathesis:1992-75198
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 21:48
• Last Modified: 19 Nov 2019 21:48
• URI: https://theses.gla.ac.uk/id/eprint/75198