SEVERE HYPERTRIGLYCERIDEMIA, REDUCED HIGH-DENSITY-LIPOPROTEIN, AND NEONATAL DEATH IN LIPOPROTEIN-LIPASE KNOCKOUT MICE - KNOCKOUT MICE MILD HYPERTRIGLYCERIDEMIA WITH IMPAIRED VERY-LOW-DENSITY LIPOPROTEIN CLEARANCE IN HETEROZYGOTES

Lipoprotein lipase (LPL)-deficient mice have been created by gene targ eting in embryonic stem cells, At birth, homozygous knockout pups have threefold higher triglycerides and sevenfold higher VLDL cholesterol levels than controls, When permitted to suckle, LPL-deficient mice bec ome pale, then cyanotic, and finally die at similar to 18 h of age, Be fore death, triglyceride levels are severely elevated (15,087+/-3,805 vs, 188+/-71 mg/dl in controls), Capillaries in tissues of homozygous knockout mice are engorged with chylomicrons, This is especially signi ficant in the lung where marginated chylomicrons prevent red cell cont act with the endothelium, a phenomenon which is presumably the cause o f cyanosis and death in these mice, Homozygous knockout mice also have diminished adipose tissue stores as well as decreased intracellular f at droplets, By crossbreeding with transgenic mice expressing human LP L driven by a muscle-specific promoter, mouse lines were generated tha t express LPL exclusively in muscle but not in any other tissue, This tissue-specific LPL expression rescued the LPL knockout mice and norma lized their lipoprotein pattern, This supports the contention that hyp ertriglyceridemia caused the death of these mice and that LPL expressi on in a single tissue was sufficient for rescue, Heterozygous LPL knoc kout mice survive to adulthood and have mild hypertriglyceridemia, wit h 1.5-2-fold elevated triglyceride levels compared with controls in bo th the fed and fasted states on chow, Western-type, or 10% sucrose die ts, In vivo turnover studies revealed that heterozygous knockout mice had impaired VLDL clearance (fractional catabolic rate) but no increas e in transport rate, In summary, total LPL deficiency in the mouse pre vents triglyceride removal from plasma, causing death in the neonatal period, and expression of LPL in a single tissue alleviates this probl em, Furthermore, half-normal levels of LPL cause a decrease in VLDL fr actional catabolic rate and mild hypertriglyceridemia, implying that p artial LPL deficiency has physiological consequences.