Journal of Lipid Research, Vol 36, 1453-1462, Copyright © 1995 by Lipid Research, Inc.
Transgenic mouse model for estrogen-regulated lipoprotein metabolism: studies on apoVLDL-II expression in transgenic mice
E Zsigmond, MK Nakanishi, FE Ghiselli and L Chan
Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
We have produced transgenic mice that express an estrogen-responsive avian
apolipoprotein, apoVLDL-II. An apoVLDL-II natural gene construct containing
4.7 kb of 5' flanking and 19 bp of 3' flanking sequences together with the
4 exon/3 intron structural gene was expressed in a liver-specific manner in
transgenic mice. A single injection of estrogen caused a 5.9- to 7.5-fold
stimulation of apoVLDL-II mRNA in the liver. The transgene mRNA had the
same initiation sites of transcription as the native mRNA isolated from
laying hen liver, and the same sites were used before and after estrogen
treatment. The number of hepatocytes that stain positive for immunoreactive
apoVLDL-II increased from < 1% to 40-60% in 24 h after estrogen
treatment. Thus, in trangenic mice as in the cockerel, hepatocytes are
biochemically heterogeneous and induction of apoVLDL-II synthesis occurs by
recruitment of hepatocytes. In the plamsa compartment, compared to
controls, transgenic mice have a 3- to 5-fold higher basal total plasma
triglyceride which was accounted for by a 5.4-fold high basal VLDL
triglyceride. Estrogen treatment results in a approximately 2-fold increase
in the VLDL triglycerides over basal levels and 8.5-fold increase over
nontransgenic mice, which did not show any change in VLDL in response to
estrogen. Transgenic mice with the integrated apoVLDL-II gene provide a
useful model for the study of the regulation of lipoprotein metabolism by
estrogen.
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