Metabolic Studies in Familial Hypercholesterolemia

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

Watanabe

Kita

1982

Self Cite

118

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...

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

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

Watanabe

Kita

1982

Self Cite

118

“…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)(2)(3). The apparent synthetic rate for LDL-protein also tends to be increased (1,2,4).…”

mentioning

confidence: 99%

“…Kinetic parameters for disappearance of LDL were calculated by the two-pool model of Matthews (18). The apoprotein concentration of LDL (apo-LDL) was calculated from the measured value for Chol associated with the LDL fraction (LDL-Chol) and the measured ratio of protein to Chol in each subject's LDL (2,15). RESULTSAll of the patients had family histories consistent with FH and plasma levels of LDL-Chol in the heterozygote range ( Table 1).…”

mentioning

confidence: 99%

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

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

Grundy²,

Brown³

et al. 1983

460

146

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...

Normal Cholesterol Levels With Lovastatin (Mevinolin) Therapy in a Child With Homozygous Familial Hypercholesterolemia Following Liver Transplantation

East

Grundy²,

1986

JAMA

Patients with homozygous familial hypercholesterolemia produce no normal low-density lipoprotein (LDL) receptors, and as a result, LDL accumulates in plasma, causing severe premature atherosclerosis. Two years ago, liver transplantation was performed in a child with homozygous familial hypercholesterolemia, restoring LDL receptor activity to about 60% of normal and reducing the LDL cholesterol level by 81%. However, the patient's lipoprotein levels remained significantly elevated for her age and sex. Treatment with lovastatin (mevinolin) one year after transplantation produced a marked improvement in the patient's lipoprotein profile. The total and LDL cholesterol levels fell 40% and 49%, respectively, to values within the normal range. The level of very low-density lipoprotein cholesterol fell 41%, and the level of total triglycerides declined 28%. While lovastatin therapy decreased the production rate of LDL by 35%, it did not affect the LDL fractional clearance rate. Thus, the combination of liver transplantation and lovastatin restored total and LDL cholesterol levels to normal in this patient with homozygous familial hypercholesterolemia.