We have also reported that atorvastatin can improve triglyceride-rich lipoprotein metabolism in insulin resistance by decreasing plasma concentrations of apoB-48, apoC-III and RLP-cholesterol, as well as by increasing the FCR of IDL-apoB and chylomicron remnants

We have also reported that atorvastatin can improve triglyceride-rich lipoprotein metabolism in insulin resistance by decreasing plasma concentrations of apoB-48, apoC-III and RLP-cholesterol, as well as by increasing the FCR of IDL-apoB and chylomicron remnants.120,124,125 The efficacy of statins in improving chylomicron remnant metabolism clearance may depend on their potency in inhibiting HMG-CoA reductase, for we have found that pravastatin, a weaker statin than atorvastatin, does not significantly alter plasma apoB-48 levels or the FCR Kdr of chylomicron remnant-like emulsion in type 2 diabetes (Watts GF et al. use of stable isotope tracers and mathematical modelling. Knowledge of the pathophysiology of lipoprotein metabolism in the metabolic syndrome is usually well complemented by extensive cell biological data. Nutritional modifications and increased physical exercise may favourably alter lipoprotein transport in the metabolic syndrome by collectively decreasing the hepatic secretion of VLDL-apoB and the catabolism of HDL apoA-I, as well as by increasing the clearance of LDL-apoB. Pharmacological treatments, such as statins, fibrates or fish oils, can also correct the dyslipidaemia by several mechanisms of action including decreased secretion and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. The complementary mechanisms of action of lifestyle and drug therapies support the use of combination regimens to treat dyslipidaemia in the metabolic syndrome. Introduction Visceral obesity, insulin resistance, dyslipidaemia, hypertension and a pro-inflammatory/thrombotic state SBI-477 collectively define SBI-477 the metabolic syndrome.1,2 Individuals with themetabolic syndrome have a significant increase in cardiovascular morbidity and mortality.3C5 A recent estimate of the prevalence of the metabolic syndrome suggests that 25% of adults in the United States have this condition.6,7 Recognising its clinical importance, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III has recently identified the metabolic syndrome as a secondary target of therapy for the management of cardiovascular disease (CVD) beyond LDL-cholesterol lowering.1 Dyslipidaemia is probably the major mediator of atherogenicity in the metabolic syndrome.8,9 This review focuses on the dysregulation and therapeutic regulation of lipoprotein transport in non-diabetic subjects with the metabolic syndrome from studies chiefly carried out with stable isotopes. We also place the human work within the context of contemporary molecular and cell biological studies that have contributed to knowledge in this field. Defining the Metabolic Syndrome: Importance of Dyslipidaemia To aid research and clinical practice, several definitions SBI-477 of the metabolic syndrome have been proposed by various expert groups.1,10,11 The individual definitions are given in Table 1. Despite the different definitions, dyslipidaemia (specifically, high plasma triglycerides and low HDL-cholesterol concentrations) is usually a common feature of all the definitions given in Table 1. The prevalence of the metabolic syndrome including dyslipidaemia increases from normal, through IGT to diabetes. However, within populations most subjects with the metabolic syndrome do not have diabetes mellitus.3 The importance of dyslipidaemia is evidenced by prospective epidemiological data showing that it is a major, independent risk factor for coronary heart disease (CHD) within the metabolic syndrome.9 Dyslipidaemia also incrementally increases the risk of CHD in diabetes.12 Table 1 Clinical definitions of the metabolic syndrome. Open in a separate window Tracer Studies of Lipoprotein Metabolism Measurements of plasma lipid and lipoprotein concentrations are static estimates traditionally employed to characterise disorders of lipoprotein metabolism. However, lipoprotein metabolism is complex and abnormal plasma concentrations can result from alterations in the rates of production and/or catabolism of the various lipoprotein particles.13 Tracer studies, whether utilising radioactive or stable isotopes, provide data from which mechanistic, kinetic models can be developed and tested against experimental data. 14 Such models can provide novel insight to further understanding of metabolic disorders and effects of treatments. Radioisotope tracers were employed SBI-477 to review lipoprotein kinetics previously, 15C17 but this process had several methodological disadvantages and was bio-hazardous potentially.18 Advancements in gas chromatography-mass spectrometry (GCMS) technology and widespread option of inexpensive, steady isotopes have observed the increasing usage of endogenous labelling of apoproteins with amino acidity precursor molecules to review lipoprotein kinetics in human beings.18C22 Steady isotopically-labelled proteins (typically 13C-leucine or D3-leucine) could be administered intravenously like a bolus or primed infusion with serial bloodstream sampling over several hours/times to review the turnover of VLDL, intermediate- density lipoprotein (IDL) and LDL-apoB, aswell mainly because HDL A-II and apoA-I. Enrichment data are generated by GCMS evaluation after separation from the relevant apoproteins. The info are after that put through multicompartmental evaluation to measure the fractional transformation and turnover prices of lipoproteins, from which total transport prices are calculated. Normal choices to assess apoA and apoB kinetics are shown in Shape 1. Full methodological information on the aforementioned methods are provided in a number of of our magazines.19,23C26 Steady isotope and multicompartmental analysis enable you to research the turnover of chylomicron remnants also, triglycerides, cholesterol and essential fatty acids.27C30 Open up in another window Shape 1 Compartment model explaining apoB-100 (a), apoA-I.