COOH-TERMINAL DISRUPTION OF LIPOPROTEIN-LIPASE IN MICE IS LETHAL IN HOMOZYGOTES, BUT HETEROZYGOTES HAVE ELEVATED TRIGLYCERIDES AND IMPAIREDENZYME-ACTIVITY

The role of the enzyme lipoprotein Lipase (LPL) in atherosclerosis is uncertain. To generate an animal model of LPL deficiency, we targeted the LPL gene in embryonic stem cells with a vector designed to disrupt the COOH terminus of the protein and used these cells to generate LPL -deficient mice, Germ line transmission of the disrupted LPL allele wa s achieved with two chimeric males, and offspring from each of these a nimals were phenotypically identical. Pups homozygous (-/-) for LPL de ficiency died within 48 h of birth with extreme elevations of serum tr iglycerides (13,327 mg/dl) associated with essentially absent LPL enzy me activity in heart and carcass. Newborn heterozygous (+/-) LPL-defic ient pups had lower LPL enzyme activity and higher triglycerides (370 versus 121 mg/dl) than wild type (+/+) littermates. Adult heterozygote s had higher triglycerides than mild type mice with ad libitum feeding (236 mg/dl for +/- versus 88 mg/dl for +/+) and after fasting for 4 h (98 mg/dl for +/- versus 51 for +/+) or 12 h (109 mg/dl for +/- versu s 56 mg/dl for +/+), Triglycerides mere present as very low density Li poprotein particles and chylomicrons, but high density lipoprotein cho lesterol levels were not decreased in +/- animals. Plasma heparin-rele asable LPL activity was 43% lower in +/- versus +/+ adult animals. LPL activity, mRNA, and protein were lower in the tissues of +/- versus /+ mice. Homozygous LPL deficiency caused by disruption of the COOH te rminus of the enzyme is lethal in mice, Heterozygous LPL deficiency ca used by this mutation is associated with mild to moderate hypertriglyc eridemia without affecting static HDL cholesterol levels. Heterozygous LPL-deficient mice could be useful for determining if hypertriglyceri demia, independently or in combination with other discrete defects, in fluences atherosclerosis.