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J Clin Invest. 1993 Aug; 92(2): 883–893.
PMCID: PMC294927

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.

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  • Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986 Apr 4;232(4746):34–47. [PubMed]
  • Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622–630. [PubMed]
  • Ji ZS, Brecht WJ, Miranda RD, Hussain MM, Innerarity TL, Mahley RW. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells. J Biol Chem. 1993 May 15;268(14):10160–10167. [PubMed]
  • Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445–466. [PubMed]
  • Watanabe Y, Ito T, Shiomi M. The effect of selective breeding on the development of coronary atherosclerosis in WHHL rabbits. An animal model for familial hypercholesterolemia. Atherosclerosis. 1985 Jul;56(1):71–79. [PubMed]
  • Scanu AM, Khalil A, Neven L, Tidore M, Dawson G, Pfaffinger D, Jackson E, Carey KD, McGill HC, Fless GM. Genetically determined hypercholesterolemia in a rhesus monkey family due to a deficiency of the LDL receptor. J Lipid Res. 1988 Dec;29(12):1671–1681. [PubMed]
  • Soutar AK, Myant NB, Thompson GR. The metabolism of very low density and intermediate density lipoproteins in patients with familial hypercholesterolaemia. Atherosclerosis. 1982 Jun;43(2-3):217–231. [PubMed]
  • Kita T, Brown MS, Bilheimer DW, Goldstein JL. Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5693–5697. [PMC free article] [PubMed]
  • Hobbs HH, Leitersdorf E, Leffert CC, Cryer DR, Brown MS, Goldstein JL. Evidence for a dominant gene that suppresses hypercholesterolemia in a family with defective low density lipoprotein receptors. J Clin Invest. 1989 Aug;84(2):656–664. [PMC free article] [PubMed]
  • Lamon-Fava S, Jimenez D, Christian JC, Fabsitz RR, Reed T, Carmelli D, Castelli WP, Ordovas JM, Wilson PW, Schaefer EJ. The NHLBI Twin Study: heritability of apolipoprotein A-I, B, and low density lipoprotein subclasses and concordance for lipoprotein(a). Atherosclerosis. 1991 Nov;91(1-2):97–106. [PubMed]
  • Spady DK, Woollett LA, Dietschy JM. Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids. Annu Rev Nutr. 1993;13:355–381. [PubMed]
  • Higuchi K, Kitagawa K, Kogishi K, Takeda T. Developmental and age-related changes in apolipoprotein B mRNA editing in mice. J Lipid Res. 1992 Dec;33(12):1753–1764. [PubMed]
  • Scott J. The molecular and cell biology of apolipoprotein-B. Mol Biol Med. 1989 Feb;6(1):65–80. [PubMed]
  • Chan L. Apolipoprotein B, the major protein component of triglyceride-rich and low density lipoproteins. J Biol Chem. 1992 Dec 25;267(36):25621–25624. [PubMed]
  • Van't Hooft FM, Hardman DA, Kane JP, Havel RJ. Apolipoprotein B (B-48) of rat chylomicrons is not a precursor of the apolipoprotein of low density lipoproteins. Proc Natl Acad Sci U S A. 1982 Jan;79(1):179–182. [PMC free article] [PubMed]
  • Chowdhury JR, Grossman M, Gupta S, Chowdhury NR, Baker JR, Jr, Wilson JM. Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits. Science. 1991 Dec 20;254(5039):1802–1805. [PubMed]
  • Wilson JM, Grossman M, Wu CH, Chowdhury NR, Wu GY, Chowdhury JR. Hepatocyte-directed gene transfer in vivo leads to transient improvement of hypercholesterolemia in low density lipoprotein receptor-deficient rabbits. J Biol Chem. 1992 Jan 15;267(2):963–967. [PubMed]
  • Hofmann SL, Russell DW, Brown MS, Goldstein JL, Hammer RE. Overexpression of low density lipoprotein (LDL) receptor eliminates LDL from plasma in transgenic mice. Science. 1988 Mar 11;239(4845):1277–1281. [PubMed]
  • Pathak RK, Yokode M, Hammer RE, Hofmann SL, Brown MS, Goldstein JL, Anderson RG. Tissue-specific sorting of the human LDL receptor in polarized epithelia of transgenic mice. J Cell Biol. 1990 Aug;111(2):347–359. [PMC free article] [PubMed]
  • Yokode M, Hammer RE, Ishibashi S, Brown MS, Goldstein JL. Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors. Science. 1990 Nov 30;250(4985):1273–1275. [PubMed]
  • Herz J, Gerard RD. Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2812–2816. [PMC free article] [PubMed]
  • Stratford-Perricaudet LD, Levrero M, Chasse JF, Perricaudet M, Briand P. Evaluation of the transfer and expression in mice of an enzyme-encoding gene using a human adenovirus vector. Hum Gene Ther. 1990 Fall;1(3):241–256. [PubMed]
  • Capecchi MR. Altering the genome by homologous recombination. Science. 1989 Jun 16;244(4910):1288–1292. [PubMed]
  • Yokode M, Pathak RK, Hammer RE, Brown MS, Goldstein JL, Anderson RG. Cytoplasmic sequence required for basolateral targeting of LDL receptor in livers of transgenic mice. J Cell Biol. 1992 Apr;117(1):39–46. [PMC free article] [PubMed]
  • Willnow TE, Goldstein JL, Orth K, Brown MS, Herz J. Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem. 1992 Dec 25;267(36):26172–26180. [PubMed]
  • Goldstein JL, Basu SK, Brown MS. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 1983;98:241–260. [PubMed]
  • Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, Russell DW. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984 Nov;39(1):27–38. [PubMed]
  • Mehta KD, Chen WJ, Goldstein JL, Brown MS. The low density lipoprotein receptor in Xenopus laevis. I. Five domains that resemble the human receptor. J Biol Chem. 1991 Jun 5;266(16):10406–10414. [PubMed]
  • Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991 Feb 22;64(4):693–702. [PubMed]
  • Mansour SL, Thomas KR, Capecchi MR. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988 Nov 24;336(6197):348–352. [PubMed]
  • McMahon AP, Bradley A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell. 1990 Sep 21;62(6):1073–1085. [PubMed]
  • Russell DW, Schneider WJ, Yamamoto T, Luskey KL, Brown MS, Goldstein JL. Domain map of the LDL receptor: sequence homology with the epidermal growth factor precursor. Cell. 1984 Jun;37(2):577–585. [PubMed]
  • Yamada N, Shames DM, Takahashi K, Havel RJ. Metabolism of apolipoprotein B-100 in large very low density lipoproteins of blood plasma. Kinetic studies in normal and Watanabe heritable hyperlipidemic rabbits. J Clin Invest. 1988 Dec;82(6):2106–2113. [PMC free article] [PubMed]
  • Yamada N, Shames DM, Havel RJ. Effect of low density lipoprotein receptor deficiency on the metabolism of apolipoprotein B-100 in blood plasma. Kinetic studies in normal and Watanabe heritable hyperlipidemic rabbits. J Clin Invest. 1987 Aug;80(2):507–515. [PMC free article] [PubMed]
  • Pittman RC, Carew TE, Attie AD, Witztum JL, Watanabe Y, Steinberg D. Receptor-dependent and receptor-independent degradation of low density lipoprotein in normal rabbits and in receptor-deficient mutant rabbits. J Biol Chem. 1982 Jul 25;257(14):7994–8000. [PubMed]
  • Spady DK, Huettinger M, Bilheimer DW, Dietschy JM. Role of receptor-independent low density lipoprotein transport in the maintenance of tissue cholesterol balance in the normal and WHHL rabbit. J Lipid Res. 1987 Jan;28(1):32–41. [PubMed]
  • Bilheimer DW, Stone NJ, Grundy SM. Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo. J Clin Invest. 1979 Aug;64(2):524–533. [PMC free article] [PubMed]
  • James RW, Martin B, Pometta D, Fruchart JC, Duriez P, Puchois P, Farriaux JP, Tacquet A, Demant T, Clegg RJ, et al. Apolipoprotein B metabolism in homozygous familial hypercholesterolemia. J Lipid Res. 1989 Feb;30(2):159–169. [PubMed]
  • Havel RJ, Kita T, Kotite L, Kane JP, Hamilton RL, Goldstein JL, Brown MS. Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia. Arteriosclerosis. 1982 Nov-Dec;2(6):467–474. [PubMed]
  • Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992 Oct 16;258(5081):468–471. [PubMed]
  • Plump AS, Smith JD, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343–353. [PubMed]
  • Schaefer EJ, Gregg RE, Ghiselli G, Forte TM, Ordovas JM, Zech LA, Brewer HB., Jr Familial apolipoprotein E deficiency. J Clin Invest. 1986 Nov;78(5):1206–1219. [PMC free article] [PubMed]
  • Kovanen PT, Brown MS, Basu SK, Bilheimer DW, Goldstein JL. Saturation and suppression of hepatic lipoprotein receptors: a mechanism for the hypercholesterolemia of cholesterol-fed rabbits. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1396–1400. [PMC free article] [PubMed]
  • Spady DK, Dietschy JM. Interaction of dietary cholesterol and triglycerides in the regulation of hepatic low density lipoprotein transport in the hamster. J Clin Invest. 1988 Feb;81(2):300–309. [PMC free article] [PubMed]
  • Ginsberg HS, Moldawer LL, Sehgal PB, Redington M, Kilian PL, Chanock RM, Prince GA. A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1651–1655. [PMC free article] [PubMed]
  • Kowal RC, Herz J, Goldstein JL, Esser V, Brown MS. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5810–5814. [PMC free article] [PubMed]
  • Holmquist L, Carlson K, Carlson LA. Comparison between the use of isopropanol and tetramethylurea for the solubilisation and quantitation of human serum very low density apolipoproteins. Anal Biochem. 1978 Aug 1;88(2):457–460. [PubMed]

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