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.
We have produced transgenic mice expressing human lipoprotein lipase (LPL) driven by the mouse metallothionein I promoter. We found that integration of the LPL gene construct was associated with a high perinatal mortality. Animals that survived the first 2 weeks of life grew normally afterwards. Compared with controls, transgenic animals had higher post-heparin plasma LPL and tissue LPL activities. Immunoreactive human LPL was detected in their post-heparin plasma but not in controls. Transgenic animals had significantly lower plasma very low density lipoprotein (VLDL) while on a regular laboratory chow. By electron microscopic analysis and nondenaturing polyacrylamide gradient gel electrophoresis, the size and morphology of the plasma VLDL were very similar in transgenic and control animals, which suggests that VLDL particles acted on by the increased tissue LPL in the transgenic animals were mostly taken up by the cell without being released back into circulation. The hypertriglyceridemia and elevated VLDL in response to sucrose feeding were completely abolished in transgenic animals. They also had lower VLDL lipids compared with control animals when they were fed a high-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 that the deleterious effect of LPL overexpression may be related to the depletion of some essential lipid nutrient.
Zsigmond
E
E
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030.
Scheffler
E
E
Forte
T M
TM
Potenz
R
R
Wu
W
W
Chan
L
L
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D001483:Base Sequence; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D015870:Gene Expression; D008049:Lipase / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000737:chemistry
D004040:Dietary Carbohydrates; D004041:Dietary Fats; D008079:Lipoproteins, VLDL; D015345:Oligonucleotide Probes; D008668:Metallothionein; D008049:Lipase; D008071:Lipoprotein Lipase