MODULATION OF VERY-LOW-DENSITY LIPOPROTEIN PRODUCTION AND CLEARANCE CONTRIBUTES TO AGE-DEPENDENT AND GENDER-DEPENDENT HYPERLIPOPROTEINEMIA IN APOLIPOPROTEIN-E3 LEIDEN TRANSGENIC MICE

Apolipoprotein E3-Leiden (APOE3-Leiden) transgenic mice have been stu died to identify factors modulating chylomicron and VLDL remnant lipop rotein metabolism, Transient elevated levels of VLDL/LDL-sized lipopro teins occurred in these mice with maximal levels during the period of rapid growth (optimum at 45 d of age), After about 100 d of age, serum cholesterol and triglyceride levels stabilized to slightly elevated l evels as compared to control mice. The expression of the APOE3-Leiden transgene was not age-dependent, In young mice the in vivo hepatic pr oduction of VLDL-triglycerides was 50% increased as compared to older mice. This is sustained by in vivo VLDL-apo B turnover studies showing increased (75%) VLDL-apo B secretion rates in young mice, whereas the VLDL-apo B clearance rate appeared not to be age dependent. On a high fat/cholesterol diet, females displayed significantly higher choleste rol levels than males (10 versus 7.0 mmol/liter, respectively). Serum levels of VLDL/LDL sized lipoproteins increased upon administration of estrogens, whereas administration of testosterone gave the opposite r esult, As compared to male mice, in female mice the hepatic VLDL-trigl yceride production rate was significantly elevated, Injection of estro gen in males also resulted in increased VLDL-triglyceride production, although not statistically significant, In vivo VLDL-apo B turnover ex periments showed that the VLDL secretion rate tended to be higher in f emales, Although, the fractional catabolic rate of VLDL-apo B is not d ifferent between males and females, administration of estrogens in mal es resulted in a decreased clearance rate of VLDL, whereas administrat ion of testosterone in females resulted in an increased clearance rate of VLDL. The latter presumably due to an inhibiting effect of testost erone on the expression of the APOE3-Leiden transgene. We conclude th at hyperlipidemia in APOE3-Leiden transgenic mice is strongly affecte d by age via its effect on hepatic VLDL production rate, whereas gende r influences hyperlipidemia by modulating both hepatic VLDL production and clearance rate.