TRANSGENIC MICE EXPRESSING HUMAN LIPOPROTEIN-LIPASE DRIVEN BY THE MOUSE METALLOTHIONEIN PROMOTER - A PHENOTYPE ASSOCIATED WITH INCREASED PERINATAL-MORTALITY AND REDUCED PLASMA VERY-LOW-DENSITY LIPOPROTEIN OF NORMAL SIZE
E. Zsigmond et al., TRANSGENIC MICE EXPRESSING HUMAN LIPOPROTEIN-LIPASE DRIVEN BY THE MOUSE METALLOTHIONEIN PROMOTER - A PHENOTYPE ASSOCIATED WITH INCREASED PERINATAL-MORTALITY AND REDUCED PLASMA VERY-LOW-DENSITY LIPOPROTEIN OF NORMAL SIZE, The Journal of biological chemistry, 269(29), 1994, pp. 18757-18766
We have produced transgenic mice expressing human lipoprotein lipase (
LPL) driven by the mouse metallothionein I promoter. We found that int
egration of the LPL gene construct was associated with a high perinata
l mortality. Animals that survived the first 2 weeks of life grew norm
ally afterwards. Compared with controls, transgenic animals had higher
post-heparin plasma LPL and tissue LPL activities. Immunoreactive hum
an LPL was detected in their post-heparin plasma but not in controls.
Transgenic animals had significantly lower plasma very low density lip
oprotein (VLDL) while on a regular laboratory chow. By electron micros
copic analysis and nondenaturing polyacrylamide gradient gel electroph
oresis, the size and morphology of the plasma VLDL were very similar i
n transgenic and control animals, which suggests that VLDL particles a
cted on by the increased tissue LPL in the transgenic animals were mos
tly taken up by the cell without being released bads into circulation.
The hypertriglyceridemia and elevated VLDL in response to sucrose fee
ding were completely abolished in transgenic animals. They also had lo
wer VLDL lipids compared with control animals when they were fed a hig
h-fat, high cholesterol diet. Feeding the mother of transgenic mice a
high-fat diet during pregnancy completely reversed the high perinatal
mortality associated with the integrated transgene, which suggests tha
t the deleterious effect of LPL overexpression may be related to the d
epletion of some essential lipid nutrient.