The Regulation of Triglyceride Metabolism in the Liver and Adipose Tissue

Crawford, Lynne Mary (1998) The Regulation of Triglyceride Metabolism in the Liver and Adipose Tissue. PhD thesis, University of Glasgow.

Abstract

The overall aim of this thesis is to understand better the control of triglyceride metabolism in both human and rat models. Triglyceride metabolism is governed to a large part by the action of two enzymes, lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL), whose activities are co-ordinately regulated by insulin. This thesis has two inter-related aims: firstly to investigate the effect of postprandial chylomicronaemia on the metabolism of VLDL subfractions in both normal and diabetic subjects and secondly to investigate the antilipolytic mechanism of action of several agents on HSL activity and adipocyte lipolysis in isolated primary rat adipocytes. Nicotinic acid was administered to Alderley Park (Wistar-derived) and Zucker rats to study its effects on plasma free fatty acid (FFA) levels in vivo with a view to using it as a model compound to influence the postprandial chylomicron-VLDL interaction in man. Postprandial lipoprotein metabolism has been extensively studied in normals, hypertriglyceridaemics and diabetics using oral fat loads and measuring plasma triglyceride levels. It is only in recent years that immunoaffmity chromatography techniques have been developed and implemented by a few groups, with studies concentrating on normal and hypertriglyceridaemic subjects. Twenty five diabetic subjects were screened and from those, 5 diabetic subjects agreed to take part in the fat feeding study. From the initial fasting blood sample obtained from the normal and diabetic patients during the screening procedure, plasma triglyceride, cholesterol and apoB concentrations were found to be significantly elevated (p <0.005) in the diabetic patient population. In diabetic subjects, triglyceride response curves showed similar behaviour to those observed in normal subjects with the mean plasma, apoB48, apoB100, and VLDL2 triglyceride concentrations significantly elevated (p<0.05) above fasting concentrations from 2 to 5 hours postprandially. VLDL2 triglyceride concentrations remained unchanged and relatively constant. In the latter hours of lipaemia, differences were observed between diabetic and normal subjects, diabetic triglyceride response curves were elevated and prolonged. Diabetic mean apoB100 and VLDL2 triglyceride response curves were significantly elevated above that of the normal subject group throughout the course of the experiment (0-11 hours postprandially). The increase in apoB48 TRL triglyceride was again almost 5 times greater than the increase in apoB100 TRL triglyceride. 83% of the postprandial increase in TRL (d< 1.006 g/ml) triglyceride was due to apoB48 TRL, apoB100 TRL accounted for 16%. The increase in VLDL2 triglyceride was 12 times greater than the increase in VLDL2 triglyceride. Seventy three percent of the postprandial increase in total apoB100 triglyceride was due to VLDL1, with 13% accounted for by VLDL2. Plasma insulin concentrations were significantly elevated above fasting concentrations 2 hours postprandially. Mean FFA concentrations were not increased significantly but there was a significant correlation between FFA area under the curve and apoB48 area under the curve; a relationship which failed to reach significance in the normal subjects. In vitro rat adipocyte studies to elucidate the antilipolytic mechanism of action of a series of compounds on HSL showed insulin to be the most potent antilipolytic agent, nicotinic acid (and analogues) were found to be Gi receptor agonists (depending on adenosine removal to exert their antilipolytic effect), and compound 304205 was observed to be a direct inhibitor of HSL. Thiazolidinediones (TZD), fibrates and a beta3 agonist had no inhibitory effects on HSL activity in the isolated rat adipocyte. Studies administering nicotinic acid to Zucker rats were conducted and allowed the in vivo antilipolytic effects of nicotinic acid, primarily on plasma FFA concentrations, to be observed. This thesis extends the current knowledge of the regulation of triglyceride metabolism, namely the effects of postprandial chylomicronaemia on VLDL subfraction metabolism in normal and diabetic subjects, and on the antilipolytic mechanism of action of a series of compounds on adipocyte lipolysis. It demonstrates that the lipid and lipoprotein responses to a fat meal in normal and NIDDM subjects depends on the fasting triglyceride concentration and not necessarily the underlying diabetic state. In vitro adipocyte work targeting HSL showed that not even the best antilipolytic agent was as potent as insulin.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Chris Packard
• Keywords: Biochemistry, Physiology
• Date of Award: 1998
• Depositing User: Enlighten Team
• Unique ID: glathesis:1998-75917
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 17:37
• Last Modified: 19 Nov 2019 17:37
• URI: https://theses.gla.ac.uk/id/eprint/75917