Impaired receptor-mediated catabolism of low density lipoprotein in the WHHL rabbit, an animal model of familial hypercholesterolemia

Bilheimer, David W.; Watanabe, Yoshio; Kita, Toru

doi:10.1073/pnas.79.10.3305

Cited by 118 publications

(74 citation statements)

References 26 publications

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“…32 As in human homozygotes, 31 the rate of production of apo B in LDL of WHHL rabbits is severalfold higher than in normal rabbits. 33 The rate of hepatic secretion of VLDL, IDL, or both may be increased as well.…”

Section: Discussionmentioning

confidence: 99%

Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia.

et al. 1982

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Section: Discussionmentioning

confidence: 99%

Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia.

et al. 1982

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“…18 . 17 rabbits exhibit massive hypercholesterolemia and moderate hypertriglyceridemia 20 and develop extensive lesions of atherosclerosis.…”

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confidence: 99%

Lipid composition of aorta of Watanabe heritable hyperlipemic and comparably hypercholesterolemic fat-fed rabbits. Plasma lipid composition determines aortic lipid composition of hypercholesterolemic rabbits.

et al. 1988

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Aortic and plasma lipid compositions were compared during a 12-month period in Watanabe heritable hyperlipemic (WHHL), comparably hypercholesterolemic fat-fed, and age-matched control normolipidemic rabbits to determine whether exposure to equivalent degrees of endogenous or exogenous hypercholesterolemia led to differences in the composition and concentration of lipids deposited in the artery wall. Although there were marked differences in the distribution of cholesterol among the Iipoproteins in the WHHL versus the fat-fed rabbits, the contents of both free and esterified cholesterol were elevated to an equivalent degree in the aorta and plasma. In contrast, the trigiyceride content of both the plasma and aorta were elevated only in the WHHL rabbits. However, aortic total phospholipids were increased in both the WHHL and fat-fed animals as compared to control rabbits. In the control rabbits, there was an agedependent enrichment in aortic relative to plasma cholesteryl-oleate consistent with low density Iipoprotein (LDL) receptor-directed intracellular cholesteryl ester processing. In contrast, enrichment in cholesteryloleate in aortae relative to plasma was not detected in either WHHL or fat-fed groups, suggesting that the plasma cholesteryl ester composition was the primary determinant of the aortic cholesterol composition. Thus, during chronic hypercholesterolemia, deposition of lipids in the artery wall appears to be determined by plasma Iipoprotein levels and composition if the LDL receptor is either absent on a genetic basis or suppressed due to a high-fat, high-cholesterol diet. E arly studies focusing on the lipid composition of the atherosclerotic plaque in fat-fed rabbits demonstrated increases in free and esterified cholesterol and phospholipids.1 -4 The arterial lipid composition was similar to that in plasma, suggesting that it was derived from the plasma. 56 The source of the increased arterial lipids in rabbits, swine, and humans has now been clearly demonstrated to be the plasma Iipoproteins, 7 -15 in particular low density Iipoproteins (LDL). However, to date the role played by Iipoprotein receptors in directly influencing lipid deposition and composition in the artery wall is unclear.The Watanabe heritable hyperlipemic rabbit (WHHL) is an animal model of homozygous familial hypercholesterolemia. 18 . 17 rabbits exhibit massive hypercholesterolemia and moderate hypertriglyceridemia 20 and develop extensive lesions of atherosclerosis. 21 The hypercholesterolemia in rabbits that results from cholesterol feeding also leads to the formation of atherosclerotic lesions and may lead to down-regulation in the number of functional LDL receptors. 22 This study examines the composition of both arterial wall and plasma lipids in WHHL, comparably hypercholesterolemic fat-fed (FF), and age-matched control rabbits to determine whether a reduction in the number of functional LDL receptors influences the amount and type of lipids deposited in the arteries during chronic hypercholesterolemia. Methods Rabbit Co...

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“…A second aliquot of the original LDL (5 mg of LDL-protein) was kept at 4°C for 60-70 hr and then radiolabeled with 131I (131I-LDL) (15). Native 131I-LDL and Glc-1251-LDL were sterilized by Millipore filtration, mixed, and injected into rabbits for pyrogen testing (3,15) and comparison of turnover rates (17).…”

mentioning

confidence: 99%

Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.

Bilheimer

Grundy²,

Brown³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

459

146

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In subjects with heterozygous familial hypercholesterolemia (FH), a 50% deficiency of receptors for plasma low density lipoprotein (LDL) impairs the removal of LDL from plasma and produces hypercholesterolemia. In these patients mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, blocks cholesterol synthesis and lowers plasma LDL levels. To determine the mechanism for the LDL-lowering effect, we administered 1311_ labeled LDL intravenously to six FH heterozygotes before and during treatment with mevinolin and calculated the apparent fractional catabolic rate (FCR) and synthetic rate for LDL. After mevinolin treatment, the mean plasma LDL-cholesterol level declined from 262 to 191 mg/dl (27% decrease), the mean FCR for 1311-labeled LDL increased from 0.30 to 0.41 pools per day (37% increase), and the mean calculated synthetic rate for LDL-protein did not change significantly. In one FH heterozygote with an ileal bypass and in another who received colestipol, the addition of mevinolin caused, respectively, a 41% and 60% decrease in plasma LDL levels and a 60% and 100% increase in the FCR for plasma LDL. The contribution of receptor-dependent pathways to the FCR for plasma LDL was estimated in three FH heterozygotes by simultaneous measurements of the FCR for native '3'I-labeled LDL and '251-labeled glucosylated LDL, which does not bind to LDL receptors. Whereas the removal rate for native LDL increased after mevinolin treatment, the removal rate for glucosylated LDL did not change. The current data suggest that mevinolin alone or mevinolin plus bile acid depletion (i.e., ileal bypass or colestipol therapy) decreases plasma LDL levels primarily by raising the number of LDL receptors and, thus, enhancing the removal of LDL from plasma.Patients with heterozygous familial hypercholesterolemia (FH) have one mutant gene and one normal gene specifying the cell surface receptor for plasma low density lipoprotein (LDL) (1). This receptor normally mediates the cellular uptake and degradation of LDL in liver and extrahepatic tissues. FH heterozygotes produce, on average, one-half the normal number of LDL receptors (1) and remove LDL from plasma at about twothirds the normal rate (1-3). The apparent synthetic rate for LDL-protein also tends to be increased (1, 2, 4).In cultured human fibroblasts, the synthesis of LDL receptors is under feedback regulation (5). Under normal conditions of growth, cells from normal subjects and from FH heterozygotes express only about 10% of the maximal number of receptors (6). In FH heterozygote cells, as in normal cells, production of receptors is stimulated when the cells are deprived of exogenous cholesterol and the cellular content of cholesterol (Chol) declines (6). A similar feedback regulation of receptor synthesis appears to operate in vivo. Thus, when FH heterozygotes are treated with the bile acid-binding resin cholestyramine, receptor-mediated catabolism of plasma LDL increases and the level of plasma LDL declines (7). This increase in receptor activity is p...

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Impaired receptor-mediated catabolism of low density lipoprotein in the WHHL rabbit, an animal model of familial hypercholesterolemia

Cited by 118 publications

References 26 publications

Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia.

Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia.

Lipid composition of aorta of Watanabe heritable hyperlipemic and comparably hypercholesterolemic fat-fed rabbits. Plasma lipid composition determines aortic lipid composition of hypercholesterolemic rabbits.

Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.

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