The Regulation of Hepatic Lipoprotein Metabolism in the St Thomas' Mixed Hyperlipidaemic Rabbit

Ardern, Hazel Alison (1999) The Regulation of Hepatic Lipoprotein Metabolism in the St Thomas' Mixed Hyperlipidaemic Rabbit. PhD thesis, University of Glasgow.

Abstract

The aim of this thesis was to characterise further the lipoprotein abnormalities present in the St Thomas' Mixed Hyperlipidaemic (SMHL) rabbit, assess the suitability of this strain as an animal model for the human disorder familial combined hyperlipidaemia, and to investigate the genetic defect giving rise to the disorder. The SMHL rabbit colony was derived from the original St Thomas' Hospital rabbit colony, first described in 1987 as exhibiting elevated plasma cholesterol, plasma triglyceride or both. Indirect evidence for overproduction of VLDL and LDL apoB as the underlying metabolic defect was obtained. To investigate lipoprotein metabolism in these rabbits further, we made use of techniques already in place in our laboratory, developed a liver perfusion method and took advantage of new molecular biological techniques for mRNA quantitation. All studies were performed on rabbits fed a 0.08% cholesterol diet, which was found to exaggerate an already dyslipidaemic phenotype in the SMHL rabbits. Plasma cholesterol levels were found to be elevated in both young and mature male SMHL rabbits in comparison to NZW controls (p < 0.001, p = 0.04 respectively). Plasma triglyceride levels were elevated in young SMHL rabbits compared to young NZW (p < 0.001), but there was no difference between the strains in mature rabbits. These changes were found to be as a result of an increased mass of each of the lipoproteins studied: very low density lipoprotein (VLDL)1, VLDL2, intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), (Sf 60 - 400, Sf 20 - 60, Sf 12 - 20 and Sf 0 - 12 respectively) but there was no alteration in lipoprotein composition or apolipoprotein content. The SMHL rabbits exhibited insulin resistance with exaggerated free fatty acid (FFA) and insulin responses to an oral glucose dose. Cholesteryl ester transfer protein (CETP) activities were increased 3 fold in the SMHL rabbits (p < 0.01), but there were no differences in hepatic lipase (HL) or lipoprotein lipase (LPL) activities. Investigation of the kinetics of lipoprotein metabolism using stable isotope labelling of apoB, yielded poor results due to the assays being at the limit of detection. There were no significant differences in production rates or catabolic rates of any of the lipoprotein species, however, trends towards increased VLDL1 and IDL production, and decreased IDL catabolism were seen. To investigate directly the output of apoB containing lipoproteins from the liver of the SMHL rabbits, we developed a method to perfuse the rabbit livers. This involved the perfusion of the organ for 3 hours with a recirculating, oxygenated Krebs Henseleit buffer at 37

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Keith Suckling
• Keywords: Medicine, Physiology
• Date of Award: 1999
• Depositing User: Enlighten Team
• Unique ID: glathesis:1999-75494
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 19:38
• Last Modified: 19 Nov 2019 19:38
• URI: https://theses.gla.ac.uk/id/eprint/75494