Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.
We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-/- mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type litter-mates, owing to a seven- to ninefold increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for intravenously administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of 125I-HDL was normal in the LDLR-/- mice. Unlike wild-type mice, LDLR-/- mice responded to moderate amounts of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR-/- mice was reduced to normal 4 d after the intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. We conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.
Ishibashi
S
S
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235.
Brown
M S
MS
Goldstein
J L
JL
Gerard
R D
RD
Hammer
R E
RE
Herz
J
J
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D008074:Lipoproteins / Q000097:blood; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D011973:Receptors, LDL / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D011995:Recombination, Genetic; D015183:Restriction Mapping; D013234:Stem Cells / Q000378:metabolism
D002791:Cholesterol, Dietary; D008074:Lipoproteins; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D009838:Oligodeoxyribonucleotides; D011973:Receptors, LDL; D002784:Cholesterol