[Truncated abstract] Dyslipidaemia in obesity and the metabolic syndrome is typically characterized by elevated plasma concentrations of apolipoprotein (apo) B and chylomicron remnants, and low apoA-I levels. This may account for the increased risk of cardiovascularrelated diseases. Although the precise mechanisms whereby visceral obesity confers the onset of dyslipidaemia have not been fully established, it may relate chiefly to insulin resistance. Insulin resistance leads to increased hepatic secretion of very low density lipoprotein (VLDL) apoB, as well as impaired catabolism of VLDL, intermediate density lipoprotein (IDL), low-density lipoprotein (LDL) and chylomicron remnants, and high density lipoprotein (HDL) apoA-I. This thesis tests the unifying hypothesis that lipoprotein metabolism, in particular apoB, chylomicron remnants and apoA-I, is abnormal in the metabolic syndrome, and that medical intervention can correct for these abnormalities. The primary objectives were to examine firstly, the kinetics of apoB and apoA-I by stable isotope technology and secondly, chylomicron remnant kinetics by using an indirect assessment of a new breath test. Six observational statements and related hypotheses were constructed and derived from the unifying hypothesis that examine the kinetics of lipoprotein metabolism, adipose tissue mass compartments and liver fat accumulation, as well as the impact of plasma adipocytokines in subjects with visceral adiposity and features of the metabolic syndrome. The first four observational statements related to cross-sectional studies of lipoprotein kinetics, adipose tissue mass distribution and liver fat accumulation as well as plasma adipocytokines in both obese and non-obese men. The latter two observational statements related to the effect of statin therapy and dietary weight loss on the improvement of lipoprotein kinetics in obesity. The findings from these studies collectively support the unifying hypothesis. The kinetics of apoB in VLDL, IDL and LDL, and apoA-I in HDL were assessed by gas-chromatography mass spectrometry following either a primed-constant infusion of 13C-leucine or an intravenous bolus injection of d3-leucine. ... This is the first study to examine the effects of dietary weight loss on LDL and HDL metabolism and the relationships with adipocytokines in men with the metabolic syndrome. The data support the unifying hypothesis that medical intervention with dietary weight loss could correct the kinetic abnormalities in VLDL, LDL and HDL. The aforementioned studies showed that plasma lipid and lipoprotein abnormalities in visceral obesity are chiefly regulated by the combination of hepatic over-secretion of VLDL particles, and catabolic defects in apoB and chylomicron remnants as well as apoA-I-containing lipoprotein particles. These kinetic defects may also relate to low and high plasma adiponectin and RBP-4 levels, respectively. The data arising from the thesis are consistent with the unifying hypothesis and support the role of dietary intervention and pharmacotherapy as a recommended treatment in correcting the abnormalities in lipoprotein metabolism within the metabolic syndrome.

[Truncated abstract] The metabolic syndrome is characterized by cardiovascular risk factors including dyslipidemia, insulin resistance, visceral obesity, hypertension and diabetes. The dyslipidemia of the metabolic syndrome includes elevated plasma triglyceride and apolipoprotein (apo) B levels, accumulation of small, dense low-density lipoprotein (LDL) particles and low high-density lipoprotein (HDL) cholesterol concentration. However, the precise mechanisms for this dyslipoproteinemia, specifically low plasma HDL cholesterol, are not well understood. This thesis therefore, focuses on HDL, its structure, function and metabolism. However, lipoprotein metabolism is a complex interconnected system, which includes forward and reverse cholesterol transport pathways. Hence, this thesis also examines and discusses the metabolism of apoB-containing lipoproteins. This thesis tests the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that lipid regulating therapies can improve these kinetic abnormalities. The aims were first, to compare and establish the clinical, metabolic and kinetic differences between metabolic syndrome and lean subjects; and second, to determine the regulatory effects of statin therapy, specifically, rosuvastatin on lipoprotein transport in the metabolic syndrome. Five observation statements were derived from the general hypothesis and examined in the studies described below. The findings are presented separately as a series of original publications. Study 1 Twelve men with the metabolic syndrome and ten lean men were studied in a case-control setting. ... These findings explain the HDL raising effects of rosuvastatin in the metabolic syndrome. Collectively, these studies suggest that the dyslipidemia of the metabolic syndrome results from increased production rates of VLDL and LDL particles, reduced fractional catabolic rates of these lipoproteins, together with accelerated catabolism of HDL particles. Treatment with rosuvastatin increases the catabolic rates of all apoB-containing lipoproteins and at a higher dose, decreases LDL apoB production. These effects are consistent with inhibition of cholesterol synthesis leading to an upregulation of LDL receptors. Rosuvastatin decreases the fractional catabolism of HDL particles. The effects of rosuvastatin on HDL kinetics may be related to a reduction in triglyceride concentration and cholesterol ester transfer protein activity. These findings are consistent with the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that statin therapy improves these kinetic abnormalities.