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Modulation of very low density lipoprotein production and clearance contributes to age- and gender- dependent hyperlipoproteinemia in apolipoprotein E3-Leiden transgenic mice.
J Clin Invest. 1996 Mar 01; 97(5):1184-92.JCI

Abstract

Apolipoprotein E3-Leiden (APOE*3-Leiden) transgenic mice have been studied to identify factors modulating chylomicron and VLDL remnant lipoprotein metabolism. Transient elevated levels of VLDL/LDL-sized lipoproteins 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 levels as compared to control mice. The expression of the APOE*3-Leiden transgene was not age-dependent. In young mice the in vivo hepatic production 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 cholesterol 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 result. As compared to male mice, in female mice the hepatic VLDL-triglyceride production rate was significantly elevated. Injection of estrogen in males also resulted in increased VLDL-triglyceride production, although not statistically significant. In vivo VLDL-apo B turnover experiments showed that the VLDL secretion rate tended to be higher in females. Although, the fractional catabolic rate of VLDL-apo B is not different between males and females, administration of estrogens in males resulted in a decreased clearance rate of VLDL, whereas administration of testosterone in females resulted in an increased clearance rate of VLDL. The latter presumably due to an inhibiting effect of testosterone on the expression of the APOE*3-Leiden transgene. We conclude that hyperlipidemia in APOE*3-Leiden transgenic mice is strongly affected by age via its effect on hepatic VLDL production rate, whereas gender influences hyperlipidemia by modulating both hepatic VLDL production and clearance rate.

Authors+Show Affiliations

TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

8636429

Citation

van Vlijmen, B J., et al. "Modulation of Very Low Density Lipoprotein Production and Clearance Contributes to Age- and Gender- Dependent Hyperlipoproteinemia in Apolipoprotein E3-Leiden Transgenic Mice." The Journal of Clinical Investigation, vol. 97, no. 5, 1996, pp. 1184-92.
van Vlijmen BJ, van 't Hof HB, Mol MJ, et al. Modulation of very low density lipoprotein production and clearance contributes to age- and gender- dependent hyperlipoproteinemia in apolipoprotein E3-Leiden transgenic mice. J Clin Invest. 1996;97(5):1184-92.
van Vlijmen, B. J., van 't Hof, H. B., Mol, M. J., van der Boom, H., van der Zee, A., Frants, R. R., Hofker, M. H., & Havekes, L. M. (1996). Modulation of very low density lipoprotein production and clearance contributes to age- and gender- dependent hyperlipoproteinemia in apolipoprotein E3-Leiden transgenic mice. The Journal of Clinical Investigation, 97(5), 1184-92.
van Vlijmen BJ, et al. Modulation of Very Low Density Lipoprotein Production and Clearance Contributes to Age- and Gender- Dependent Hyperlipoproteinemia in Apolipoprotein E3-Leiden Transgenic Mice. J Clin Invest. 1996 Mar 1;97(5):1184-92. PubMed PMID: 8636429.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of very low density lipoprotein production and clearance contributes to age- and gender- dependent hyperlipoproteinemia in apolipoprotein E3-Leiden transgenic mice. AU - van Vlijmen,B J, AU - van 't Hof,H B, AU - Mol,M J, AU - van der Boom,H, AU - van der Zee,A, AU - Frants,R R, AU - Hofker,M H, AU - Havekes,L M, PY - 1996/3/1/pubmed PY - 1996/3/1/medline PY - 1996/3/1/entrez SP - 1184 EP - 92 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 97 IS - 5 N2 - Apolipoprotein E3-Leiden (APOE*3-Leiden) transgenic mice have been studied to identify factors modulating chylomicron and VLDL remnant lipoprotein metabolism. Transient elevated levels of VLDL/LDL-sized lipoproteins 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 levels as compared to control mice. The expression of the APOE*3-Leiden transgene was not age-dependent. In young mice the in vivo hepatic production 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 cholesterol 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 result. As compared to male mice, in female mice the hepatic VLDL-triglyceride production rate was significantly elevated. Injection of estrogen in males also resulted in increased VLDL-triglyceride production, although not statistically significant. In vivo VLDL-apo B turnover experiments showed that the VLDL secretion rate tended to be higher in females. Although, the fractional catabolic rate of VLDL-apo B is not different between males and females, administration of estrogens in males resulted in a decreased clearance rate of VLDL, whereas administration of testosterone in females resulted in an increased clearance rate of VLDL. The latter presumably due to an inhibiting effect of testosterone on the expression of the APOE*3-Leiden transgene. We conclude that hyperlipidemia in APOE*3-Leiden transgenic mice is strongly affected by age via its effect on hepatic VLDL production rate, whereas gender influences hyperlipidemia by modulating both hepatic VLDL production and clearance rate. SN - 0021-9738 UR - https://www.unboundmedicine.com/medline/citation/8636429/Modulation_of_very_low_density_lipoprotein_production_and_clearance_contributes_to_age__and_gender__dependent_hyperlipoproteinemia_in_apolipoprotein_E3_Leiden_transgenic_mice_ L2 - https://doi.org/10.1172/JCI118532 DB - PRIME DP - Unbound Medicine ER -