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 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.