Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia.
Journal: 1981/August - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
PUBMED: 6264472
Abstract:
The WHHL (Watanabe heritable hyperlipidemic) rabbit has been proposed as an animal model for human familial hypercholesterolemia. Homozygous WHHL rabbits have marked increases in the plasma level of low density lipoprotein (LDL), removal of LDL from their plasma is delayed, and LDL receptors are absent from their cultured fibroblasts [Tanzawa, K., Shimada, Y., Kuroda, M., Tsujita, Y., Arai, M. & Watanabe, Y. (1980) FEBS Lett. 118, 81--84]. We here report that membranes from the liver and adrenal gland of WHHL rabbits lack high-affinity LDL receptors. In normal rabbit membranes, binding of LDL to this receptor required calcium and is inhibited by EDTA. The LDL receptor binds rabbit 125I-labeled beta-migrating very low density lipoprotein (beta-VLDL), which contains apoproteins B and E, as well as rabbit 125I-labeled LDL, which contains only apoprotein B. It does not bind high density lipoprotein or methyl-LDL. All of these properties are identical with those of the LDL receptor of cultured fibroblasts. We conclude that a deficiency of hepatic and adrenal LDL receptors contributes to the hypercholesterolemia of the WHHL rabbits.
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Proc Natl Acad Sci U S A 78(4): 2268-2272

Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia.

Abstract

The WHHL (Watanabe heritable hyperlipidemic) rabbit has been proposed as an animal model for human familial hypercholesterolemia. Homozygous WHHL rabbits have marked increases in the plasma level of low density lipoprotein (LDL), removal of LDL from their plasma is delayed, and LDL receptors are absent from their cultured fibroblasts [Tanzawa, K., Shimada, Y., Kuroda, M., Tsujita, Y., Arai, M. & Watanabe, Y. (1980) FEBS Lett. 118, 81--84]. We here report that membranes from the liver and adrenal gland of WHHL rabbits lack high-affinity LDL receptors. In normal rabbit membranes, binding of LDL to this receptor required calcium and is inhibited by EDTA. The LDL receptor binds rabbit 125I-labeled beta-migrating very low density lipoprotein (beta-VLDL), which contains apoproteins B and E, as well as rabbit 125I-labeled LDL, which contains only apoprotein B. It does not bind high density lipoprotein or methyl-LDL. All of these properties are identical with those of the LDL receptor of cultured fibroblasts. We conclude that a deficiency of hepatic and adrenal LDL receptors contributes to the hypercholesterolemia of the WHHL rabbits.

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  • Brown MS, Goldstein JL. Familial hypercholesterolemia: model for genetic receptor disease. Harvey Lect. 1979;73:163–201. [PubMed] [Google Scholar]
  • Goldstein JL, Brown MS. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem. 1977;46:897–930. [PubMed] [Google Scholar]
  • Ho YK, Brown S, Bilheimer DW, Goldstein JL. Regulation of low density lipoprotein receptor activity in freshly isolated human lymphocytes. J Clin Invest. 1976 Dec;58(6):1465–1474.[PMC free article] [PubMed] [Google Scholar]
  • Bilheimer DW, Ho YK, Brown MS, Anderson RG, Goldstein JL. Genetics of the low density lipoprotein receptor. Diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia. J Clin Invest. 1978 Mar;61(3):678–696.[PMC free article] [PubMed] [Google Scholar]
  • Kovanen PT, Brown MS, Goldstein JL. Increased binding of low density lipoprotein to liver membranes from rats treated with 17 alpha-ethinyl estradiol. J Biol Chem. 1979 Nov 25;254(22):11367–11373. [PubMed] [Google Scholar]
  • Windler EE, Kovanen PT, Chao YS, Brown MS, Havel RJ, Goldstein JL. The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins B and E. J Biol Chem. 1980 Nov 10;255(21):10464–10471. [PubMed] [Google Scholar]
  • Kovanen PT, Goldstein JL, Chappell DA, Brown MS. Regulation of low density lipoprotein receptors by adrenocorticotropin in the adrenal gland of mice and rats in vivo. J Biol Chem. 1980 Jun 25;255(12):5591–5598. [PubMed] [Google Scholar]
  • Kovanen PT, Bilheimer DW, Goldstein JL, Jaramillo JJ, Brown MS. Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1194–1198.[PMC free article] [PubMed] [Google Scholar]
  • 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] [Google Scholar]
  • Kondo T, Watanabe Y. A heritable hyperlipemic rabbit. Jikken Dobutsu. 1975 Jul;24(3):89–94. [PubMed] [Google Scholar]
  • Watanabe Y. Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit). Atherosclerosis. 1980 Jun;36(2):261–268. [PubMed] [Google Scholar]
  • Tanzawa K, Shimada Y, Kuroda M, Tsujita Y, Arai M, Watanabe H. WHHL-rabbit: a low density lipoprotein receptor-deficient animal model for familial hypercholesterolemia. FEBS Lett. 1980 Aug 25;118(1):81–84. [PubMed] [Google Scholar]
  • Innerarity TL, Pitas RE, Mahley RW. Receptor binding of cholesterol-induced high-density lipoproteins containing predominantly apoprotein E to cultured fibroblasts with mutations at the low-density lipoprotein receptor locus. Biochemistry. 1980 Sep 2;19(18):4359–4365. [PubMed] [Google Scholar]
  • Weisgraber KH, Innerarity TL, Mahley RW. Role of lysine residues of plasma lipoproteins in high affinity binding to cell surface receptors on human fibroblasts. J Biol Chem. 1978 Dec 25;253(24):9053–9062. [PubMed] [Google Scholar]
  • Bilheimer DW, Eisenberg S, Levy RI. The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972 Feb 21;260(2):212–221. [PubMed] [Google Scholar]
  • Kovanen PT, Schneider WJ, Hillman GM, Goldstein JL, Brown MS. Separate mechanisms for the uptake of high and low density lipoproteins by mouse adrenal gland in vivo. J Biol Chem. 1979 Jun 25;254(12):5498–5505. [PubMed] [Google Scholar]
  • Basu SK, Goldstein JL, Brown MS. Characterization of the low density lipoprotein receptor in membranes prepared from human fibroblasts. J Biol Chem. 1978 Jun 10;253(11):3852–3856. [PubMed] [Google Scholar]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  • Brown MS, Faust JR, Goldstein JL. Role of the low density lipoprotein receptor in regulating the content of free and esterified cholesterol in human fibroblasts. J Clin Invest. 1975 Apr;55(4):783–793.[PMC free article] [PubMed] [Google Scholar]
  • Mahley RW, Weisgraber KH, Innerarity T. Canine lipoproteins and atherosclerosis. II. Characterization of the plasma lipoproteins associated with atherogenic and nonatherogenic hyperlipidemia. Circ Res. 1974 Nov;35(5):722–733. [PubMed] [Google Scholar]
  • Goldstein JL, Ho YK, Brown MS, Innerarity TL, Mahley RW. Cholesteryl ester accumulation in macrophages resulting from receptor-mediated uptake and degradation of hypercholesterolemic canine beta-very low density lipoproteins. J Biol Chem. 1980 Mar 10;255(5):1839–1848. [PubMed] [Google Scholar]
  • Dana SE, Brown MS, Goldstein JL. Specific, saturable, and high affinity binding of 125I-low density lipoprotein to glass beads. Biochem Biophys Res Commun. 1977 Feb 21;74(4):1369–1376. [PubMed] [Google Scholar]
  • Ross AC, Zilversmit DB. Chylomicron remnant cholesteryl esters as the major constituent of very low density lipoproteins in plasma of cholesterol-fed rabbits. J Lipid Res. 1977 Mar;18(2):169–181. [PubMed] [Google Scholar]
Abstract
The WHHL (Watanabe heritable hyperlipidemic) rabbit has been proposed as an animal model for human familial hypercholesterolemia. Homozygous WHHL rabbits have marked increases in the plasma level of low density lipoprotein (LDL), removal of LDL from their plasma is delayed, and LDL receptors are absent from their cultured fibroblasts [Tanzawa, K., Shimada, Y., Kuroda, M., Tsujita, Y., Arai, M. & Watanabe, Y. (1980) FEBS Lett. 118, 81--84]. We here report that membranes from the liver and adrenal gland of WHHL rabbits lack high-affinity LDL receptors. In normal rabbit membranes, binding of LDL to this receptor required calcium and is inhibited by EDTA. The LDL receptor binds rabbit 125I-labeled beta-migrating very low density lipoprotein (beta-VLDL), which contains apoproteins B and E, as well as rabbit 125I-labeled LDL, which contains only apoprotein B. It does not bind high density lipoprotein or methyl-LDL. All of these properties are identical with those of the LDL receptor of cultured fibroblasts. We conclude that a deficiency of hepatic and adrenal LDL receptors contributes to the hypercholesterolemia of the WHHL rabbits.
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