High density lipoprotein metabolism in health and disease

Atmeh, Ragheb Fuad (1982) High density lipoprotein metabolism in health and disease. PhD thesis, University of Glasgow.

Abstract

High density lipoprotein increasingly attracts the attention of investigators working in the atherosclerosis field due to the reported negative correlation found between its plasma levels and the incidence of ischaemic heart disease. However, the present classification of HDL depends on the flotation properties of its subfractions, but such fractions may not represent distinct biological entities. This project sets out to sub-fractionate HDL according to its apoprotein content rather than its flotation density, and to investigate the metabolism of these subfractions under a variety of conditions. Moreover, the effects of two hypol ipidaemic drugs on HDL metabolism are studied in a group of hypertriglyceridaemic patients. HDL is prepared from normolipidaemic females and subfractionated by means of immunoaffinity chromatography. The physical and chemical properties of the isolated subfractions are studied and three methods for their quantitation presented. The distribution of these subfractions in plasma and in HDL density subclasses is studied in the normal state, during nicotinic acid and probucol therapy. Mathematical analysis of the tracer decay data is also discussed. The results of these studies are summarised as follows: 1. HDL can be subfractionated into two meta-bolically distinct types of particles, i.e., those containing primarily apo-AI without apo-AII and those with both apoproteins. Both species are detectable and have been quantified in fresh plasma and in HDL density subclasses. It is found that HDL2 from normal young females contain a higher proportion of the (AI)HDL particles (71%) than HDL3 (43%). Moreover, it is demonstrated that minimal exchange of A apoproteins seems to occur between the two types of particles. 2. The kinetic behaviour of (AI)HDL is, generally, similar to that of total HDL. On the other hand, their apoproteins show inconsistent deviations in the locations of their catabolism. Evidence for intravascular and extravascular site of catabolism is discussed. 3. Nicotinic acid is shown to have a reciprocal effect on (AI)HDL and (AI/AII)HDL. It raised the plasma levels of the former by 20% (p<0.05) and lowered those of the latter by 19.5% (p<0.05). A similar effect was observed on HDL2 and HDL3 concentrations. The former rose by 45% (p<0.01) and the latter fell by 28% (p<0.01) during treatment with the drug. The rise in the former was attributable in its entirety to an increase of its (AI)HDL content (20%, p<0.01). 4. Probucol, unlike nicotinic acid, lowers the plasma concentration of (AI)HDL by 22% (p<0.01) and of HDL2 by 58% (p<0.05) but it has no consistent effect on either (AI/AII)HDL or HDL3. The drop in HDL3 level is mainly a result of a reduction in its (AI)HDL content. In hypertriglyceridaemia the drug reduced the plasma levels of apo-AI , apo-AII and HDL. The decrease in the latter is due mainly to a fall in the HDL3 level. This was associated with a reduction in the plasma level of apo-AII due to a fall in its rate of synthesis. Moreover, the treatment with the drug affected the composition of HDL where its cholesterol content was decreased with a concomitant increase in the protein content. 5. Bezafibrate shows little influence on HDL metabolism. 6. Examination of three mathematical approaches for tracer data analysis, i.e., curve peeling (Matthews), multicompartmental (Berman) and graphical integration (Nosslin) methods, showed that the same value of the total fractional catabolic rate of HDL can be obtained by any of these procedures. In addition, calculation of the extravascular catabolic rate can be done by the last two methods which produced similar results.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: J Shepherd
• Keywords: Medicine
• Date of Award: 1982
• Depositing User: Enlighten Team
• Unique ID: glathesis:1982-72017
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 May 2019 13:23
• Last Modified: 17 May 2019 13:23
• URI: https://theses.gla.ac.uk/id/eprint/72017