High plasma triglycerides (TG) are independent and better predictors of cardiovascular disease (CVD) than low-density lipoprotein (LDL) cholesterol in women (1), suggesting that treatment of hypertriglyceridemia may be more important in women. This finding may be related to differences in lipid metabolism between genders. Women are at a lower risk of cardiovascular disease than men until they are postmenopausal, when the risk is similar (2). The reason for this is not clear but may be related to the increase in fat in postmenopausal women rather than the loss of ovarian hormones (3). Obesity is one of the major risk factors for the development of CVD in both men and women (4). In young lean subjects, it has been shown that very-low-density lipoprotein (VLDL)-TG production by the liver is higher in women than men, but because clearance was also much higher in women, this resulted in lower plasma TG in women than men (5). In young obese men, VLDL-TG production was higher than in young obese women, and clearance was similar in the two groups, also resulting in lower plasma TG in women than men (6). Although these studies clearly indicate there are major differences in lipoprotein metabolism in men and women, if we are to understand why plasma TG is a better predictor of CVD in women, VLDL kinetics studies need to be undertaken in men and women matched for plasma TG concentration. VLDL secreted by the liver can be divided into the large TG-rich VLDL1 and the smaller more dense TG-poor VLDL2. There is evidence that these two VLDL species are independently regulated (7). The first step in VLDL assembly is the formation of a partially assembled primordial particle (pre-VLDL). This is formed when apolipoprotein B100 is cotranslationally lipidated in the endoplasmic reticulum by microsomal transfer protein. Pre-VLDL can either be retained and degraded or further lipidated to form VLDL2. This particle is transported to the Golgi and can then either be secreted or converted to the large TG-rich form, VLDL1, after the addition of more TG. The hydrolysis of VLDL1-TG by lipoprotein lipase also generates VLDL2. Thus, VLDL2 has two sources. All of the studies to date that have investigated VLDL1-TG and VLDL2-TG kinetics have been in men (8, 9). VLDL1 and VLDL2 apolipoprotein B kinetics have been investigated in men and women combined in a single group (10), but no studies have examined gender differences in VLDL1 and VLDL2 kinetics. The regulation of VLDL production is governed partly by the intracellular availability of lipid substrates for lipoprotein assembly (11, 12). The production of free fatty acids (FFA) from adipose tissue has been shown to be greater in young lean women than men even when they are matched for adiposity (13). Although FFA concentrations have been reported to be higher in women (14), the difference is small, and many studies find no difference in FFA concentrations (15). This suggests that FFA clearance from the circulation must also be higher in women than men. The increased delivery of FFA to liver may lead to increased VLDL-TG production in women. Using stable isotope techniques, this study has investigated in postmenopausal obese women and men matched for age, body mass index (BMI), and fasting plasma TG whether there are differences in VLDL1-TG and VLDL2-TG production and clearance rate, FFA production, and oxidation rate. |