Cholestyramine Promotes Receptor-Mediated Low-Density-Lipoprotein Catabolism

Shepherd, James; Packard, C.J.; Bicker, S; Lawrie, T. D. V.; Morgan, Hugh

doi:10.1056/nejm198005293022202

Cited by 358 publications

(121 citation statements)

References 15 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…The specific Fractional Catabolic Rate of native LDL (0.72 pool/day) is similar to that of OL-NME-LDL (0.70 pool/day). These values are in accordance with Shepherd et al (1980). Several other methods have been described for the incorporation of lipophilic cytotoxic drug into LDL (see Shaw et al, 1988, for targeting could lead to increased exposure of OL-NME to the tumour and consequently, increase the antitumour efficacy.…”

Section: Discussionsupporting

confidence: 81%

“…The labelled lipoproteins were then freed of unbound radioiodide and glycine buffer by exhaustive dialysis against 0.15 M NaCI/0.01% Na2EDTA, pH 7, followed by gel filtration through Sephadex G25 PD-10 column (Pharmacia, France). The {f31I-LDL} were treated with 1,2-cyclohexanedione as described elsewhere (Shepherd et al, 1979;Mahley et al, 1977), to block the charge on the arginyl residues of its protein moiety. Cyclohexanedione-modified LDL (CHD-LDL) prepared in this way has been fully characterised previously (Slater et al, 1982).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Low density lipoprotein for cytotoxic drug targeting: improved activity of elliptinium derivative against B16 melanoma in mice

Samadi-Baboli

Favre²,

Canal³

et al. 1993

Br J Cancer

View full text Add to dashboard Cite

Summary Significant low density lipoprotein (LDL) uptake by tumour cells led to the use of LDL as a discriminatory vehicle for the delivery of cytotoxic drugs. In the current study, the lipophilic elliptinium derivative, elliptinium-oleate (OL-NME), was incorporated into LDL to reach an incorporation level of 400 molecules per LDL particle. The OL-NME-LDL complex showed cytotoxic effects on normal human fibroblasts while the cytotoxicity was not observed on receptor-defective human fibroblasts, indicating the ability of the complex to be preferentially metabolised by the LDL receptor. In vivo metabolism of the complex was related to the LDL receptor pathway. The metabolic clearance was the same for native LDL (17.1 ml h-') and OL-NME-LDL complex (16.2 ml h'). LDL incorporated OL-NME enhanced the antitumour activity against murine B16 melanoma model; this resulted from increased efficacy for OL-NME-LDL at doses equal to free 9-OH-NME (157 vs 76 of Increase Life Span (ILS) (%) values after intraperitoneal (i.p.) drug injection on i.p. implanted tumour model and 45 vs -2 ILS (%) values after intravenous drug injection on subcutaneous implanted tumour model). These data suggest that LDL improves the potency of lipophilic cytotoxic drugs against tumours that express LDL receptor activity.

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Low density lipoprotein for cytotoxic drug targeting: improved activity of elliptinium derivative against B16 melanoma in mice

Samadi-Baboli

Favre²,

Canal³

et al. 1993

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…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 postulated to result from a-decrease in the hepatic content of Chol as a result of cholestyramine's ability to bind bile acids in the intestine and prevent their reabsorption.…”

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

View full text Add to dashboard Cite

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...

show abstract

“…The latter include methyl-LDL and cyclohexandione-LDL which do not bind to the LDL receptor (5)(6)(7)(8)(9)(10)(11). In these studies, native and chemically modified LDL-each radiolabeled with a different isotope of iodine-are simultaneously injected into animals or humans and the fractional catabolic rate (FCR) for each is determined.…”

mentioning

confidence: 99%

“…Such studies in normal humans indicate that 20-50% of the total FCR for LDL is attributable to the LDL receptor (5,8). In FH heterozygotes with about half the normal number of LDL receptors, the portion of the FCR for LDL attributable to the LDL receptor drops to about halfofthe nonnal value (5,6), and in FH homozygotes essentially no LDL is cleared via the LDL receptor (8). Similar studies in normal rats, monkeys, and rabbits indicate that the LDL receptor mechanism accounts for "50% of the total FCR for LDL in these species (7,(9)(10)(11) The publication costs ofthis article were defrayed in part by page charge payment.…”

mentioning

confidence: 99%

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

Bilheimer

Watanabe

Kita

1982

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

118

View full text Add to dashboard Cite

The homozygous WHHL (Watanabe heritable hyperlipidemic) rabbit displays either no or only minimal low density lipoprotein (LDL) receptor activity on cultured fibroblasts and liver membranes and has therefore been proposed as an animal model for human familial hypercholesterolemia. To assess the impact of this mutation on LDL metabolism in vivo, we performed lipoprotein turnover studies in normal and WHHL rabbits using both native rabbit LDL and chemically modified LDL (i.e., methyl-LDL) that does not bind to LDL receptors. The total fractional catabolic rate (FCR) for LDL in the normal rabbit was 3.5-fold greater than in the WHHL rabbit. Sixty-seven percent of the total FCR for LDL in the normal rabbit was due to LDL receptormediated clearance and 33% was attributable to receptor-independent processes; in the WHHL rabbit, essentially all ofthe LDL was catabolized via receptor-independent processes. Despite a 17.5-fold elevated plasma pool size of LDL apoprotein (apo-LDL) in WHHL as compared to normal rabbits, the receptor-independent FCR-as judged by the turnover of methyl-LDL-was similar in the two strains. Thus, the receptor-independent catabolic processes are not influenced by the mutation affecting the LDL receptor. The WHHL rabbits also exhibited a 5.6-fold increase in the absolute rate of apo-LDL synthesis and catabolism. In absolute terms, the WHHL rabbit cleared 19-fold more apo-LDL via receptor-independent processes than did the normal rabbit and cleared virtually none by the receptor-dependent pathway. These results indicate that the homozygous WHHL rabbit shares a number of metabolic features in common with human familial hypercholesterolemia and should serve as a useful model for the study of altered lipoprotein metabolism associated with receptor abnormalities. We also noted that the in vivo metabolic behavior of human and rabbit LDL in the normal rabbit differed such that the mean total FCR for human LDL was only 64% of the mean total FCR for rabbit LDL, whereas human and rabbit methyl-LDL were cleared at identical rates. Thus, if human LDL and methyl-LDL had been used in these studies, the magnitude of both the total and receptor-dependent FCR would have been underestimated.Familial hypercholesterolemia (FH) is a human disease characterized clinically by accelerated atherosclerosis, elevated plasma levels of low density lipoprotein (LDL), xanthoma formation in tendons and skin, and inheritance as an autosomal dominant trait with a gene-dosage effect (1, 2). The defect is biochemically defined-by the absence or near-absence of LDL receptors on cells obtained from patients with the homozygous form of the disease and half the normal number of LDL receptors on the cells of heterozygotes (1, 2). One major result of diminished or absent LDL receptor activity is an impaired rate of LDL catabolism in vivo; on average, heterozygotes catabolize LDL at a fractional rate that is two-thirds of normal, whereas homozygotes catabolize LDL at a rate only one-third of normal (3). These results led to the p...

show abstract

Cholestyramine Promotes Receptor-Mediated Low-Density-Lipoprotein Catabolism

Cited by 358 publications

References 15 publications

Low density lipoprotein for cytotoxic drug targeting: improved activity of elliptinium derivative against B16 melanoma in mice

Low density lipoprotein for cytotoxic drug targeting: improved activity of elliptinium derivative against B16 melanoma in mice

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

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

Contact Info

Product

Resources

About