The Role of the Reticuloendothelial System in LDL Metabolism

Gibson, Stewart A. W (1985) The Role of the Reticuloendothelial System in LDL Metabolism. PhD thesis, University of Glasgow.

Abstract

Prospective epidemiological studies show that raised plasma cholesterol is a major risk factor for the development of ischaemic heart disease. Recent evidence indicates that reducing plasma cholesterol concentration reduces risk from the disease. Cholesterol is transported in the plasma mainly by low density lipoproteins (LDL) and these particles also confer risk if present in high concentrations. It is important to determine the mechanisms by which LDL is removed from the plasma and catabolised by the tissues of the body. The arterial wall is especially important in this respect as it can accumulate excessive quantities of cholesterol. LDL catabolism is divided into two pathways: 1) LDL-receptor-dependent catabolism is now a well understood process by which a receptor recognises apolipoprotein B (the sole apolipoprotein moiety on LDL) and mediates the internalisation of the lipoprotein. It is then transported to the lysosome, degraded and the cholesterol released for cellular needs. The pathway is autoregulated by cellular requirements for the sterol. In most animals, including man, approximately one half of LDL catabolism occurs by this route. 2) LDL-receptor-independent catabolism is less well defined. Studies have indicated that the reticuloendothelial system plays a role in this scavenger pathway. The purpose of the present study is to increase understanding of the role played by the reticuloendothelial system (RE system) in LDL metabolism. However, because the RE system is a disseminated tissue it is not as easy to study as, for example, the liver which can even be removed from the animal intact. One approach to this problem is functionally to block the cells of the system by injection of material which will be phagocytoced by these macrophages. This was achieved using three agents; a) ethyl oleate emulsion, b) muramyl tripeptide incorporated into triolein emulsion and c) muramyl dipeptide conjugated to acetylated bovine serum albumin (for which the cells of the RE system have a receptor). The end result was the same regardless of the agent employed. The following summarises the essential conclusions of the thesis. 1) The RE system is important in lipoprotein catabolism. Blockage of the system causes an increase in plasma triglyceride and cholesterol levels. The raised total cholesterol is almost entirely accounted for by an increase in LDL cholesterol. 2) RE cells are important in the clearance of LDL from the plasma. Administration of RE cell activity inhibiting agents causes a decrease in the rate of the clearance of the lipoprotein. Kinetic analysis shows that this was due to a decrease in LDL-receptor-independent catabolism. 3) Lipoprotein catabolism by cultured macrophages is down regulated by RE system suppressants. Incubation of macrophages with these agents reduces the amount of LDL and B-VLDL catabolised by the cells. This supports the in vivo findings. 4) LDL is altered in the plasma of RE blocked animals. It has an increased density, an increased electrophoretic mobility (negative charge, an increased cholesterol to protein ratio and is sleared from the plasma more rapidly than normal LDL. Control LDL injected into RE suppressed animals assumes the characteristics of this abnormal lipoprotein. 5) Blocking the RE system of cholesterol fed animals appears to promote the atheromatous infiltration of their aortae. Plasma cholesterol levels in the RE blocked animals were not significantly different from those in cholesterol fed animals with functional RE systems but the overall negative charge of their LDL was greater. 6) It follows that the RE system is working to clear an abnormal form of LDL which may be formed by "ageing" in the circulation. Potentially this LDL is catabolised by atherosclerotic plaques leading to lesion advancement.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Biochemistry, Physiology
• Date of Award: 1985
• Depositing User: Enlighten Team
• Unique ID: glathesis:1985-77378
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jan 2020 11:53
• Last Modified: 14 Jan 2020 11:53
• URI: https://theses.gla.ac.uk/id/eprint/77378