title: Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.
abstract: Lipoprotein lipase (LPL)-deficient mice have been created by gene targeting 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 become pale, then cyanotic, and finally die at approximately 18 h of age. Before 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 significant in the lung where marginated chylomicrons prevent red cell contact with the endothelium, a phenomenon which is presumably the cause of cyanosis and death in these mice. Homozygous knockout mice also have diminished adipose tissue stores as well as decreased intracellular fat droplets. By crossbreeding with transgenic mice expressing human LPL driven by a muscle-specific promoter, mouse lines were generated that express LPL exclusively in muscle but not in any other tissue. This tissue-specific LPL expression rescued the LPL knockout mice and normalized their lipoprotein pattern. This supports the contention that hypertriglyceridemia caused the death of these mice and that LPL expression in a single tissue was sufficient for rescue. Heterozygous LPL knockout mice survive to adulthood and have mild hypertriglyceridemia, with 1.5-2-fold elevated triglyceride levels compared with controls in both the fed and fasted states on chow, Western-type, or 10% sucrose diets. In vivo turnover studies revealed that heterozygous knockout mice had impaired VLDL clearance (fractional catabolic rate) but no increase in transport rate. In summary, total LPL deficiency in the mouse prevents triglyceride removal from plasma, causing death in the neonatal period, and expression of LPL in a single tissue alleviates this problem. Furthermore, half-normal levels of LPL cause a decrease in VLDL fractional catabolic rate and mild hypertriglyceridemia, implying that partial LPL deficiency has physiological consequences.
authors.affiliation: Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York 10021, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: Weinstock
authors.forename: C L
authors.initials: CL
authors.lastname: Bisgaier
authors.forename: K
authors.initials: K
authors.lastname: Aalto-Setälä
authors.forename: H
authors.initials: H
authors.lastname: Radner
authors.forename: R
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: S
authors.initials: S
authors.lastname: Levak-Frank
authors.forename: A D
authors.initials: AD
authors.lastname: Essenburg
authors.forename: R
authors.initials: R
authors.lastname: Zechner
authors.forename: J L
authors.initials: JL
authors.lastname: Breslow
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D015139:Blotting, Southern; D001823:Body Composition; D002784:Cholesterol / Q000097:blood; D004247:DNA / Q000032:analysis; D003643:Death; D005260:Female; D005838:Genotype; D006579:Heterozygote; D015228:Hypertriglyceridemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007408:Intestinal Absorption; D008071:Lipoprotein Lipase / Q000172:deficiency* / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000097:blood*; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D011247:Pregnancy; D013234:Stem Cells; D014280:Triglycerides / Q000097:blood*; D014801:Vitamin A / Q000378:metabolism
chemical_list: D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D014280:Triglycerides; D014801:Vitamin A; D004247:DNA; D002784:Cholesterol; D008071:Lipoprotein Lipase