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

Havel, Richard J.; Kita, Toru; Kotite, Leila; Kane, John P.; Hamilton, Robert L.; Goldstein, Joseph L.; Brown, Michael S.

doi:10.1161/01.atv.2.6.467

Cited by 124 publications

(56 citation statements)

References 33 publications

(23 reference statements)

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“…25 By contrast, Type III hyperiipoproteinemia-a condition that predisposes to premature atherosclerosis-is characterized by strikingly elevated plasma apo E levels that accumulate in intermediate sized lipoproteins (fraction II). 27 ' M An increased mass of apo E in partially catabolized VLDL, IDL, and LDL is also found in certain animal models of atherosclerosis such as the WHHL rabbit 9 and cholesterol-fed monkeys, dogs, and swine. 12 It has been suggested 29 that apo E-containing intermediate sized lipoproteins are atherogenic by virtue of their capacity to deliver cholesterol to macrophage precursors of atherosclerotic foam cells via surface receptors specifically recognizing apo E.…”

Section: Discussionmentioning

confidence: 99%

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Plasma lipoprotein distribution of apolipoprotein E in familial hypercholesterolemia.

Gibson

Goldberg²,

Rubinstein

et al. 1987

Arteriosclerosis

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Although familial hypercholesterolemia (FH) has been well characterized in terms of the etiology of the major lipoprotein abnormality, that of low density llpoproteins (LDL), less Information is available on changes in other llpoproteins which could Influence the atherogenlc process In this disorder. The present study has focused on such potential abnormalities by studying In detail the lipoprotein association of apolipoprotein E (apo E) In a large group of subjects homozygous for FH. Total plasma apo E levels In homozygous subjects were significantly elevated (p< 0.001) relative to heterozygous subjects which were, In turn, significantly greater (p<0.001) than controls ( As a result, LDL catabolism is impaired, LDL synthesis is increased, and patients homozygous for this gene (FHH) manifest a massive accumulation of LDL cholesterol. Although this LDL elevation is the most obvious lipoprotein abnormality, several studies have described subtle abnormalities in the metabolism of other lipoproteins or apolipoproteins. For example, very low density lipoprotein (VLDL) metabolism and structure appear normal, but intermediate density lipoprotein (IDL) catabolism has been shown to be retarded.2 High density lipoprotein (HDL) abnormalities have also been documented in FHH. Specifically, reduced levels of HDL that are nearly devoid of the HDL 2 subclass have been documented. 3With respect to the plasma apolipoproteins, apolipopro-

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Section: Discussionmentioning

confidence: 99%

“…8 The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of FHH, also has elevated plasma apo E levels. 9 The lipoprotein association of apo E, however, has not been described in this disorder. Apo E is normally a component of VLDL, IDL, and HDL subclasses.…”

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confidence: 96%

Plasma lipoprotein distribution of apolipoprotein E in familial hypercholesterolemia.

Gibson

Goldberg²,

Rubinstein

et al. 1987

Arteriosclerosis

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“…In contrast, the absence of a protein identical to intestinal B-48 in human prebeta VLDL, IDL, and LDL weighs heavily against the possibility that this protein is secreted by human liver. Again, the rat may be unusual among mammals in this respect because the VLDL of guinea pigs, 47 rabbits, 48 and monkeys (L.L. Rudel, personal communication) contain no B-48 proteins.…”

Section: Discussionmentioning

confidence: 99%

Remnants of lipoproteins of intestinal and hepatic origin in familial dysbetalipoproteinemia.

Kane¹,

Chen²,

Hamilton³

et al. 1983

Arteriosclerosis

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102

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We used the low molecular weight form of apolipoprotein B (B-48) as a marker for the identification of remnant particles formed from chyiomicrons in the plasma of patients with familial dysbetalipoproteinemia. In the serum of patients fasted 14 hours, the d < 1.006 g/cm 3 lipoproteins of prebeta mobility, separated by starch block electrophoresis, contained only the primary hepatogenous species of apolipoprotein B (B-100), and their llpld composition resembled that of normal prebeta very low density lipoproteins. In contrast, the fraction with beta mobility contained both the B-48 and B-100 proteins; the B-48 protein was found primarily among the largest particles. All fractions of beta mobility were greatly enriched with choiesteryi esters. The beta fraction thus contains remnant particles which appear to originate both from chyiomicrons and hepatogenous very low density lipoproteins. It appears that these remnant particles share a common removal mechanism which is impaired in familial dysbetalipoproteinemia. (Arteriosclerosis 3:47-56, January/February 1983) amilial dysbetalipoproteinemia (F. dys.) (type III hyperlipoproteinemia) is now recognized as a disorder in which remnant-like particles, formed from triglyceride-rich lipoproteins, accumulate in plasma.12 Clinically, it is associated with arteriosclerosis of both the coronary and peripheral circulations. 3These remnant-like lipoprotein particles are enriched with choiesteryi esters 1 2 ' 4 and have beta mobility upon electrophoresis in agarose gel, in contrast with normal very low density lipoproteins (VLDL), which have prebeta mobility. The electrophoretic mobility of remnant particles is accounted for principally by deficiency of the C-apoproteins, which are normally the preponderant species in VLDL, with retention of appreciable quantities of less anionic apolipoprotein E (apo E). 5 The initial stages of intravascular lipolysis appear to proceed relatively normally. Removal of remnant particles from the plasma normally occurs rapidly by means of receptor-mediated endocytosis in the liver.2 In F. dys., however, there is

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“…By measuring the binding affinity of VLDL incubated with various amounts of apoE for LDL receptors on human fibroblast, we found that one-half to an equal amount of apoE to VLDL protein is required to obtain a maximal effect (H.M. and N.Y., unpublished data). Because the protein concentration of VLDL in WHHL rabbits is =30 mg/dl (11,27), we decided to inject -=30 mg of apoE.…”

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confidence: 99%

Increased clearance of plasma cholesterol after injection of apolipoprotein E into Watanabe heritable hyperlipidemic rabbits.

Yamada

Shimano

Mikami

et al. 1989

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

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Apolipoprotein E (apoE) is known to play an important role in lipoprotein metabolism. We have studied the effect of apoE on the metabolism of plasma cholesterol by injecting apoE intravenously into rabbits deficient in low density lipoprotein receptors [Watanabe heritable hyperlipidemic (WHHL) rabbits]. Approximately 30 mg of apoE was injected per rabbit; a total of five WHHL rabbits were used. One hour later, plasma cholesterol levels fell 8.3% (from 488 ± 192 to 446 ± 174 mg/dl). After 3 hr, cholesterol levels had fallen by 19% (to 392 ± 152 mg/dl). The reduced levels were maintained for at least 8 hr after injection of apoE. Cholesterol in very low density lipoproteins (VLDLs) and intermediate density lipoproteins fell rapidly during the first 2 hr after injection, followed by a reduction in the low density lipoprotein cholesterol level. Changes in apolipoprotein B levels in each lipoprotein fraction were very similar to those of cholesterol.Plasma apoE levels 3 min after injection were elevated 3-fold to 22.8 ± 6.3 mg/dl and returned to initial levels 8 hr after injection. The rate of removal of intravenously injected 1251 labeled VLDL that had been incubated with apoE was 3-fold higher than that of unmodified VLDL. From these results, we conclude that the injected apoE is incorporated into VLDLs and that VLDL particles carrying more apoE are removed from the blood more rapidly, resulting in reduced formation of low density lipoprotein and lowered cholesterol levels.Low density lipoprotein (LDL) cholesterol is mainly removed from blood plasma by hepatic LDL receptors that interact with two specific ligands on lipoproteins, apolipoprotein B-100 (apoB-100) and apolipoprotein E (apoE) (1-3). Lipoproteins rich in apoE, such as large very low density lipoprotein (VLDL) and ,B-VLDL, have a much higher affinity for LDL receptors than LDL, which contains only apoB-100 (4, 5). In addition, lipoproteins containing apoE can bind to receptors on the liver cell membranes that are responsible for the uptake of dietary cholesterol carried in chylomicron remnants (6,7). This chylomicron-remnant receptor is thought to be distinct from the LDL receptor because chylomicron remnants are normally removed from the blood in human familial hypercholesterolemia (8) and in Watanabe heritable hyperlipidemic (WHHL) rabbits deficient in LDL receptors (9).Recent research has demonstrated two lipoprotein subclasses containing apoB-100: B,E particles containing apoE and -B and B particles lacking apoE (10-12). The presence of apoE has been shown to have a profound influence on the removal of apoB-100 in VLDL particles from the blood of normal rabbits and their conversion to lipoproteins of higher density [intermediate density lipoprotein (IDL) and LDL] (10). In WHHL rabbits, the rate of removal of VLDL-B,E particles from the blood was 4-fold higher than that of VLDL-B particles (11). These results suggest that in WHHL rabbits a small number of LDL receptors expressed on the surface of hepatocytes or chylomicron-remnant receptors p...

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

Abstract: T he Watanabe-heritable hyperlipidemic (WHHL) rabbit is a strain of Japanese rabbit discovered by Watanabe which is characterized by grossly elevated levels of serum cholesterol, phospholipids, and triglycerides.

Cited by 124 publications

References 33 publications

Plasma lipoprotein distribution of apolipoprotein E in familial hypercholesterolemia.

Plasma lipoprotein distribution of apolipoprotein E in familial hypercholesterolemia.

Remnants of lipoproteins of intestinal and hepatic origin in familial dysbetalipoproteinemia.

Increased clearance of plasma cholesterol after injection of apolipoprotein E into Watanabe heritable hyperlipidemic rabbits.

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