Effects of an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase on Serum Lipoproteins and Ubiquinone-10 Levels in Patients with Familial Hypercholesterolemia

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...

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

460

146

“…Two specific inhibitors of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-CoA reductase [HMG-CoA reductase; mevalonate:NAD+ oxidoreductase (CoA-acylating), EC 1.1.1.88], mevinolin (10)(11)(12) and compactin (13)(14)(15) have recently been described. Both agents are active in milligram quantities and are potent hypocholesterolemic agents in experimental animals (12) and in both normal human volunteers (11) and patients with heterozygous FH (13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

“…Both agents are active in milligram quantities and are potent hypocholesterolemic agents in experimental animals (12) and in both normal human volunteers (11) and patients with heterozygous FH (13)(14)(15)(16)(17)(18). Because of the possibility that mevinolin, in clinically effective doses, may influence cholesterol biosynthesis in the adrenal cortex, thereby potentially leading to an impairment in adrenal corticosteroid production in patients with genetic abnormalities at the LDL receptor locus, we have evaluated the adrenal cortical response to prolonged ACTH stimulation in eight patients with well-characterized heterozygous FH studied under both basal conditions and during therapy with optimal doses of mevinolin.…”

mentioning

confidence: 99%

The influence of mevinolin on the adrenal cortical response to corticotropin in heterozygous familial hypercholesterolemia.

Illingworth¹,

Corbin²

1985

The biosynthesis of adrenal corticosteroids in humans depends on a continuous supply of cholesterol, which can be derived from both local synthesis and receptor-mediated uptake of low density lipoproteins (LDL) from plasma.Mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase [mevalonate:NAD+ oxidoreductase (CoA-acylating), EC 1.1.1.88] is an effective hypolipidemic agent in patients with heterozygous familial hypercholesterolemia. To determine whether mevinolin influences the adrenal production of corticosteroids, the adrenocortical response to a continuous 36-hr infusion of corticotropin (ACTH) was examined in eight patients with heterozygous familial hypercholesterolemia before, and again during, treatment with mevinolin (40-80 mg/day). The drug produced an average decrease of 28% and 34% in the plasma concentrations of total and LDL cholesterol. Serum cortisol levels showed similar increases in response to ACTH stimulation before and during mevinolin treatment, and the rates of excretion of urine-free cortisol were also similar. We conclude that clinically effective doses of mevinolin do not affect corticosteroid production by the adrenal cortex during prolonged ACTH stimulation in patients with heterozygous familial hypercholesterolemia.

“…The prototype compound, compactin, and its analogue, mevinolin, decrease the levels of low-density lipoprotein (LDL) in normal animals (1, 2), normal humans (3), and in heterozygotes with familial hypercholesterolemia (FH) (4)(5)(6)(7). Recently, we demonstrated that mevinolin achieves this effect by increasing the fractional rate of removal of LDL from the circulation of FH heterozygotes (7).…”

mentioning

confidence: 99%

Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase by mevinolin in familial hypercholesterolemia heterozygotes: effects on cholesterol balance.

Grundy¹,

Bilheimer²

1984

110

Patients with heterozygous familial hypercholesterolemia (FH) have a deficiency of receptors for plasma low-density lipoprotein (LDL) that impairs removal of LDL from plasma. In these patients, mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase [mevalonate:NAD' oxidoreductase (CoA-acylating), EC 1.1.1.88], increases receptors for LDL and decreases LDL concentrations. To determine whether mevinolin also causes severe decreases in total body synthesis of cholesterol, fecal excretions of neutral steroids and acidic steroids were determined in five FH heterozygotes before and during treatment with mevinolin. The drug produced an average decrease in plasma total cholesterol of 23% and in LDL cholesterol of 24%. Mevinolin caused a significant decrease in the output of neutral and acidic steroids in three patients, but it caused no alterations in two others. Changes in fecal output of steroids did not correlate with the degree of lowering of the patients' LDL-cholesterol level. In none of the patients did the output of fecal steroids fall below the values seen in normal subjects studied under similar conditions. One patient had a previous ileal exclusion operation and had a massive output of acidic steroids in the control period; mevinolin therapy caused a slight decrease in excretion of acidic steroids, but the output was still markedly above normal. We conclude that the LDL lowering action of mevinolin does not appear to require a severe decrease in cholesterol synthesis that might lead to depletion of vital body stores of cholesterol.An exciting class of drugs for treatment of hypercholesterolemia consists of fungal metabolites that are competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase [HMG-CoA reductase; mevalonate:NAD' oxidoreductase (CoA-acylating), EC 1.1.1.88], a rate-controlling enzyme in cholesterol synthesis. The prototype compound, compactin, and its analogue, mevinolin, decrease the levels of low-density lipoprotein (LDL) in normal animals (1, 2), normal humans (3), and in heterozygotes with familial hypercholesterolemia (FH) (4-7). Recently, we demonstrated that mevinolin achieves this effect by increasing the fractional rate of removal of LDL from the circulation of FH heterozygotes (7). The higher clearance rate appeared to be due to enhanced receptor-mediated catabolism of LDL.A theoretical basis for the ability of mevinolin to stimulate receptor-mediated catabolism of LDL comes from studies of human and animal cells in tissue culture. These cells have a dual source of the cholesterol required for synthesis of new membranes. Cells can synthesize cholesterol de novo in a pathway that requires the action of HMG-CoA reductase; or, the cells can obtain cholesterol from plasma LDL through endocytosis mediated by a specific LDL receptor (8).When human fibroblasts or cultured liver cells are incubated with compactin or mevinolin, HMG-CoA reductase is competitively inhibited, and the de novo synthesis of cholesterol is blocked (9, 10). This block triggers a dual regula...