Hyperlipidaemia is a well-recognised risk factor for cardiovascular disease and arises from a variety of genetic and environmental causes. Subjects with inherited hyperlipidaemias such as Familial Hypercholesterolaemia (FH) have a distinctly different phenotype from those with insulin resistance and hypertriglyceridaemia (FITG), yet both groups are predisposed to cardiovascular disease. The mechanisms whereby elevated lipids result in increased risk are still not completely understood. Lipid deposition and subsequent plaque formation in the vasculature is only part of the story. Lipids can influence plasma membrane composition and thus may affect transport mechanisms such as sodium- hydrogen exchange (NaVH.

exchange) and sodium-lithium countertransport (SLC). This may haveconsequences for cell growth and hypertrophy and could result in changes in the vessel wall which favour the development of vascular disease. Na+/H+ exchange is a well described ubiquitous transporter which has a role in maintaining intracellular pH, particularly under conditions of metabolic stress. Abnormalities of function have been described in a variety of populations including those with hypertension and diabetes, and a correlation has been found with plasma cholesterol levels. SLC is thought to operate as a sodium-sodium exchange mechanism in vivo, and despite the lack of a clear physiological role has been found to be altered in those with a family history of hypertension, in hyperlipidaemia and in individuals with known vascular disease. Many studies have been limited as kinetic parameters of SLC have not been measured. There is some evidence that the two exchange mechanisms may be related. This study describes two populations of hyperlipidaemic individuals (48 with FFI and 33 with predominantly elevated triglycerides (HTG). Full lipid profile including apoE genotype, blood pressure, BMI and glucose were examined in both groups and compared to 54 normolipaemic controls. Additionally fasting insulin levels were measured in a subgroup of the HTG population and in controls. Blood pressure and BMI were higher in both study populations than in controls. The influence of plasma lipids on the cell membrane was assessed by measurement of platelet membrane microviscosity. Membrane microviscosity as measured at the core of the membrane was reduced in HTG subjects when compared to controls of FH subjects. Microviscosity correlated with plasma triglycerides across the whole population studied, suggesting that even 'normal' triglyceride levels may influence plasma microviscosity. Sodium-hydrogen exchange was measured in lymphocytes using the fluorescent pH sensitive probe BCECF-AM. No differences were noted between the three groups. Kinetic parameters of SLC activity were calculated from the rate of lithium efflux from lithium-loaded erythrocytes into varying concentrations of sodium medium. This study confirmed higher SLC Vmax in subjects with hypertriglyceridaemia compared to normolipaemic controls. Although there was no relationship between SLC Vmax and microviscosity seen in this study, alteration of membrane fluidity by triglycerides may facilitate transporter mobility within the membrane and thus influence activity. While SLC correlated with fasting plasma glucose levels, and was higher in HTG subjects who also had higher insulin levels, this study did not provide any evidence that SLC activity is related to insulin levels or to insulin resistance. In view of the controversy as to whether SLC is a modus operandi of the NaVH+ exchanger, erythrocyte SLC activity was compared to lymphocyte Na+/H+ exchange within the same individual. There were no correlations between the transport mechanisms, although the limitations of comparing activity in different cell types is acknowledged. This study provides further evidence that SLC Vmax is influenced by plasma triglyceride levels, but does not define a role for SLC within the insulin resistance syndrome. Further work should focus on examining the relationships between plasma and membrane lipids in more detail. The lack of relationship between SLC and NaVH+ exchange serves to underline the differences between clinical studies and cell culture. The emphasis should now be on discovering the mechanism responsible for SLC (either at a genetic or protein level) in order to clarify its role in health and disease.