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PubMed1996

Effects of HMG-CoA reductase inhibitors on growth and differentiation of cultured rat skeletal muscle cells.

HMG-CoA reductase inhibitors have been associated with skeletal muscle myopathy, ranging from asymptomatic elevations of serum creatine kinase (CK) activity to rhabdomyolysis. In this study, we assessed the effects of addition of different concentrations of simvastatin and pravastatin on growth and differentiation of cultured primary rat skeletal muscle cells. Protein concentrations, CK activity and percentage CK-MM, which is a parameter for maturation, were determined. Effects were generally stronger if inhibitors were added to both growth and differentiation medium rather than only to differentiation medium. Addition of 25 microM pravastatin caused only a decrease of CK activity. Addition of 1-5 microM simvastatin resulted in a decrease of protein concentration, CK activity and percentage CK-MM, whereas 25 microM simvastatin resulted in cell death. Addition of mevalonic acid or cholesterol could not prevent the effects of 1 microM simvastatin. In addition, 1 microM simvastatin did not influence the cholesterol and phospholipid content of the cells. Superfusion of cultured cells with simvastatin concentrations of 10 microM and higher caused a transient increase of the cytoplasmic calcium concentration followed by an apparent second rise and cell puncture. The results indicate that HMG-CoA reductase inhibitors may affect skeletal muscle cell regeneration in vivo by a direct toxic effect on growth and differentiation.

Animals↗
PubMed1982

Cholesterol movement between human skin fibroblasts and phosphatidylcholine vesicles.

Cholesterol readily exchanges between human skin fibroblasts and unilamellar phospholipid vesicles. Only a fraction of the exchangeable cholesterol and only 10-15% of the total cellular free cholesterol is available for net movement or depletion to cholesterol-free phosphatidylcholine vesicles. [14C]Cholesterol introduced into the fibroblast plasma membrane by exchange from lipid vesicles does not readily equilibrate with fibroblast cholesterol labelled endogenously from [3H]mevalonic acid. While endogenously-synthesized [3H]cholesterol readily becomes incorporated into a pool of esterified cholesterol, little, if any, of the [14C]cholesterol introduced into the fibroblast membrane by exchange from lipid vesicles becomes available for esterification. We interpret these findings as suggesting that: (1) net cholesterol movement from fibroblasts to an acceptor membrane is limited to a small percentage of the plasma membrane cholesterol, and (2) separate pools of cholesterol exist in human skin fibroblasts, one associated with the plasma membrane and the second associated with intracellular membranes, and equilibration of cholesterol between the two pools is a very limited process.

Carbon Radioisotopes↗
PubMed1999

Lovastatin induces fibroblast apoptosis in vitro and in vivo. A possible therapy for fibroproliferative disorders.

Diseases associated with pathological fibroproliferation represent a major cause of morbidity and mortality. Despite the importance of this class of disorders, current therapy is of limited value, and no therapy is available to reduce the fibroblast population size within existing fibrotic lesions. In this regard, constitutive expression of growth-promoting genes can sensitize cells to undergo apoptosis. Studies in our laboratory have demonstrated that lovastatin potently induces apoptosis in fibroblasts constitutively expressing Myc, and that lung fibroblasts isolated from fibrotic lesions constitutively express growth-promoting genes. In this study, we sought to determine if nontransformed lung fibroblasts would manifest susceptibility to lovastatin-induced apoptosis similar to that observed in fibroblasts ectopically expressing Myc. Here we show that clinically achievable concentrations of lovastatin induce apoptosis in normal and fibrotic lung fibroblasts in vitro, as evidenced by acridine orange staining, terminal transferase nick end translation (TUNEL), and DNA laddering. Apoptosis of human lung fibroblasts was dose- and time-dependent, and blocked by exogenous mevalonic acid. Furthermore, apoptosis was associated with decreased levels of mature Ras, a molecule directly implicated in fibroblast rescue from apoptosis. The ability of lovastatin to induce fibroblast apoptosis in vivo was examined using a guinea pig wound chamber model. Lovastatin (5 microM, 8 d) reduced granulation tissue formation in the wound chambers by 64.7%, with associated ultrastructural evidence of fibroblast apoptosis. These findings support further study of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors as potential therapy for patients with fibroproliferative disorders.

Animals↗
PubMed1990

Isoprenylation of an inhibitory G protein alpha subunit occurs only upon mutagenesis of the carboxyl terminus.

We transfected COS cells with expression vectors for the wild-type G protein alpha i1 subunit (pWT) and for mutated alpha i1 subunits, including the nonmyristylated glycine 2 to alanine mutant (pGA) and mutants in which the carboxyl termini of pWT and pGA were changed from CGLF to CVLS (pCVLS and pGA-CVLS, respectively). Immunoblot analysis of transfected COS cells with an antibody to residues 159-168 of the alpha i1 protein indicated that all four proteins were expressed. Unlike the WT and GA proteins, both CVLS mutant proteins failed to react with an antibody specific for the carboxyl terminus and failed to undergo pertussis toxin-catalyzed ADP-ribosylation. Analysis of COS cell lysates after [3H]mevalonic acid labeling indicated that specific incorporation of radioactivity occurred only in the alpha i1 subunits with the CVLS mutation. Immuno-precipitation of COS cell fractions after labeling with [35S]methionine indicated that both WT and CVLS mutant proteins were localized predominantly in the particulate fraction, whereas GA and GA-CVLS mutant proteins were found primarily in the soluble fraction. These results directly demonstrate that the carboxyl-terminal sequence, CGLF, is incapable of leading to isoprenylation but that alteration of two residues (glycine to valine, phenylalanine to serine) is sufficient to promote isoprenylation.

Adenosine Diphosphate Ribose↗
PubMed1997

Mevalonate-dependent inhibition of transendothelial migration and chemotaxis of human peripheral blood neutrophils by pravastatin.

Pravastatin, a hydrophilic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, has been reported to beneficially affect atherogenesis, plaque stability, and transient myocardial ischemia in significant coronary artery disease by influencing lipid metabolism and by intracellular signaling via mevalonate pathway products other than cholesterol. Leukocytes are implicated to play a pathophysiological role in these events. We were interested in finding out whether pravastatin could affect transendothelial migration (TEM), chemotaxis, and respiratory burst activity of the neutrophil ex vivo. In addition, effects on monocyte and T-lymphocyte chemotaxis were tested. For TEM assays, monolayers of human umbilical vein endothelial cells (HUVECs) were grown to confluence on polycarbonate filters bearing 5-microns pores in Transwell (Costar) culture plate inserts. Chemotaxis experiments were performed using modified Boyden chambers with cellulose nitrate micropore filters. Respiratory burst activity was measured fluorometrically. Treatment of neutrophils and monocytes with pravastatin at 2 to 200 mumol/L and 10 to 1000 mumol/L, respectively, significantly decreased chemotaxis triggered by fMet-Leu-Phe. This effect was abolished in the presence of mevalonic acid (500 mumol/L); no effect of pravastatin was seen on T-lymphocyte chemotaxis triggered by interleukin-8. Preincubation of neutrophils with pravastatin (200 mumol/L) also resulted in a significant reduction in the number of neutrophils that transmigrated a tumor necrosis factor-stimulated or lipopolysaccharide-stimulated HUVEC monolayer. At none of the concentrations tested (2 pmol/L to 200 mumol/L) did pravastatin affect neutrophil respiratory burst activity. We conclude that pravastatin may alter monocyte chemotaxis and neutrophil-endothelial interactions in migratory responses at concentrations obtained in vivo with cholesterol-lowering doses.

Cell Movement↗
PubMed1995

Co-expression of native and introduced genes reveals cryptic regulation of HMG CoA reductase expression in Arabidopsis.

In eukaryotes, all isoprenoid compounds share a common precursor, mevalonic acid, whose synthesis is catalyzed by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. As one step towards a better understanding of the role that this enzyme plays in coordinating isoprenoid biosynthesis in plants, Arabidopsis thaliana HMG CoA reductase was ectopically expressed in transgenic Arabidopsis plants. By using this molecular genetic approach, several novel and fundamental observations have been made regarding isoprenoid biosynthesis in Arabidopsis. First, it was demonstrated that the overexpression of authentic Arabidopsis HMG CoA reductase is not sufficient to alter the bulk synthesis and accumulation of the abundant end products of the plant isoprenoid pathway. Second, active transcription of the transgene appears to co-activate and deregulate expression of the native gene, resulting in a striking elevation of HMG CoA reductase mRNA levels. Finally, although very high levels of HMG CoA reductase mRNA were expressed in these transgenic plants, only modest increases in enzyme activity could be detected. Taken together, these data suggest that HMG CoA reductase expression is regulated at multiple levels in plants as well as animals, and they provide a foundation for elucidating the molecular mechanisms for mevalonate regulation in A. thaliana.

Arabidopsis↗
PubMed1992

Possible mechanism and treatment of o,p'DDD-induced hypercholesterolaemia.

Ortho,para,dichlorodiphenyl dichloroethane (o,p'DDD, Mitotane (Roussell)) is used as an adrenolytic drug to reduce adrenocortical mass and circulating cortisol levels in Cushing's syndrome but has the unwanted side-effect of inducing hypercholesterolaemia. This paper examined the mechanism of that effect in 30 patients with Cushing's syndrome treated with o,p'DDD during the past 10 years. o,p'DDD increased serum cholesterol by 68 per cent, mainly by increasing LDL-cholesterol. The latter effect was not due to impaired binding of LDL to its receptor, as shown in vitro using cultured fibroblasts. Increases in plasma mevalonic acid during o,p'DDD administration were suggestive of increased cholesterol synthesis, this effect being reversed by simvastatin. These findings suggest that o,p'DDD causes hypercholesterolaemia by increasing cholesterol synthesis. It is proposed that this effect is due to the drug's known ability to block cytochrome P450-mediated reactions, thus impairing the formation of oxysterols responsible for down-regulating hepatic cholesterol synthesis. Treatment with simvastatin, an inhibitor of cholesterol synthesis, reverses the hyperlipidaemia and enables o,p'DDD therapy to be maintained without increasing cardiovascular risk.

Adult↗
PubMed1991

Evidence for sterol-independent regulation of low-density lipoprotein receptor activity in Hep-G2 cells.

The relationship between the serum factor(s)-mediated induction of low-density lipoprotein (LDL) receptor activity and changes in cellular cholesterol metabolism was examined in the human hepatoma cell line Hep-G2. Relative to incubation with serum-free media [Eagle's minimal essential medium (MEM) control], short-term (less than 8 h) incubation with medium containing 15% of either calf serum (MEM + serum) or the d greater than 1.25 fraction of calf serum (MEM + d greater than 1.25) produced a time- and concentration-dependent increase in the uptake of 125I-LDL. Immunoblotting with anti-(LDL receptor) antibodies demonstrated that this was correlated with a 2-fold increase in the amount of the mature 136,000 Da LDL receptor protein in detergent-solubilized Hep-G2 cell membranes. Incubation with MEM + serum, but not MEM + d greater than 1.25, increased the efflux of radiolabelled cholesterol from Hep-G2 cells. However, the induction of 125I-LDL uptake by MEM + d greater than 1.25 (2.3-fold) and MEM + serum (2.2-fold) was virtually identical. Addition of the d less than 1.063 lipoproteins of calf serum to MEM + d greater than 1.25 at their original or three times their serum concentration decreased the induction of 125I-LDL uptake by MEM + d greater than 1.25 by only 20-30%. Together, these results suggest that the stimulation of 125I-LDL uptake was not due to the presence of high-density lipoprotein, the absence of LDL or the stimulation of cholesterol efflux. MEM + serum stimulated 125I-LDL uptake in cells cholesterol-loaded by incubation with rat very-low-density lipoprotein with beta electrophoretic mobility (beta-VLDL). Compared to incubation with the MEM control, either MEM + serum or MEM + d greater than 1.25 produced time-dependent increases in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase which also occurred in cholesterol-loaded cells. However, cholesterol biosynthesis, whether measured from 3H2O, [14C]acetate or [3H]mevalonic acid, was not increased. Incubation with MEM + serum or MEM + d greater than 1.25 did not affect [3H]oleate incorporation into cellular cholesteryl esters, hydrolysis of intracellular [3H]cholesteryl esters or the cellular mass of unesterified or esterified cholesterol. Incubation with MEM + serum or MEM + d greater than 1.25 produced a transient increase in the level of LDL receptor mRNA, reaching a maximum of 5-10-fold by 2 h and decreasing to near baseline levels by 4 h. Actinomycin D blocked the serum-factor-mediated induction of LDL receptor mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetates↗
PubMed2004

Are iridoids in leaf beetle larvae synthesized de novo or derived from plant precursors? A methodological approach.

Iridoids, belonging to a group of cyclopentanoid monoterpenoids, are secreted by many species of leaf beetles as a defense against predators. Using chemically modified precursors of iridoid biosynthesis, it has been shown that some leaf beetle larvae can synthesize these iridoids de novo as well as sequester plant-produced molecules. Stable isotope techniques can provide useful methods for studying terpenoid biosynthesis without disturbing the natural conditions much. Two terpenoid biosynthesis pathways (mevalonic acid (MVA) pathway and methylerythritol-4-phosphate (MEP) pathway) may lead to different delta13C signatures of the products. Our results from natural abundance 13C and 13C-labelled iridoid precursors in Gastrophysa viridula and Phaedon cochleariae suggested that the two leaf beetle species use only de novo synthesis of their defensive iridoids. We observed that the isotope signature of the leaf-beetle-produced iridoids (via the MVA pathway) resembled that of the MEP-derived monoterpenoids from plants. Owing to this close similarity in the natural 13C abundances in the plant and insect compounds, a determination of iridoid-origin in leaf beetle secretion may only be possible by use of isotopically labelled compounds.

Animals↗
PubMed1991

Role of isoprenoid metabolism in IgE receptor-mediated signal transduction.

In the 2H3 subline of rat basophilic leukemia cells (RBL-2H3), IgE receptor cross-linking stimulates a signal transduction pathway that leads to the secretion of histamine, serotonin, and other inflammatory mediators; the assembly of F-actin; and the transformation of the cell surface from a microvillous to a lamellar or ruffled architecture. We report here that 20 h incubation of RBL-2H3 cells with 10 microM lovastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG CoA reductase), inhibits both the secretory and morphologic responses to IgE receptor cross-linking. Ag-induced Ca2+ mobilization, determined from the influx and efflux of 45Ca2+, and Ag-induced 1,4,5-inositol trisphosphate production are also inhibited in lovastatin-treated RBL-2H3 cells. Under the same conditions, lovastatin does not alter cell proliferation or IgE receptor expression, and it causes only a small impairment of responses initiated by drugs that bypass the earliest steps in the receptor-activated transduction pathway (ionomycin-induced secretion and PMA-induced membrane ruffling). Receptor-mediated Ca2+ mobilization, secretion, and ruffling are all restored by 0.5- to 4-h incubation of lovastatin-treated cells with mevalonic acid, the product of HMG CoA reductase and the first committed intermediate of the isoprenoid biosynthetic pathway. In contrast, dolichol and cholesterol, which are synthesized from products of the isoprenoid pathway, do not restore receptor-activated responses. These data implicate an isoprenoid pathway intermediate in an early step in the IgE receptor-activated signal-transduction sequence. We postulate that this intermediate is required for a newly described post-translational modification of proteins, their post-synthetic isoprenylation. The substrates for this modification include the ras family of GTP-binding proteins and the gamma subunits of the heterotrimeric guanine nucleotide-binding protein.

Animals↗
PubMed2000

Biosynthesis of avenacins and phytosterols in roots of Avena sativa cv. Image.

In keeping with the proposal that avenacin biosynthesis is restricted to the tips of primary roots of oat seedlings, the incorporation of radioactivity from R-[2-(14)C]mevalonic acid (MVA) into avenacins and beta-amyrin by serial sections of primary roots was found to be more-or-less restricted to root tip sections. Squalene synthase (SQS) (EC 2.5.1.21) and 2,3-oxidosqualene:beta-amyrin cyclase (OS beta AC) (EC 5.4.99) were also most active in these sections. The incorporation of radiolabel from R-[2-(14)C]MVA into cycloartenol and 24-methylene cycloartanol by, and the 2,3-oxidosqualene:cycloartenol cyclase (OSCC) (EC 5.4.99) activity in, the various serial sections were consistent with phytosterol biosynthesis occurring in all the sections of the root with some tailing-off in the rate of synthesis in the more distal sections.

Avena↗
PubMed1968

Studies in phytosterol biosynthesis. Mechanism of biosynthesis of cycloartenol.

1. The mechanism of cycloartenol biosynthesis in leaves of Solanum tuberosum was investigated with the use of [2-(14)C,(4R)-4-(3)H(1)]mevalonic acid. 2. The (3)H/(14)C atomic ratio in cycloartenol was 6:6, the same as that in squalene; this eliminates lanosterol as a possible biosynthetic precursor of cycloartenol, and indicates that a hydrogen migration from C-9 to C-8 occurs. 3. Chemical isomerization of the cycloartenol to lanosterol ((3)H/(14)C ratio 5:6) and parkeol ((3)H/(14)C ratio 6:6) confirms the hydrogen migration from C-9 to C-8. 4. Possible mechanisms for the biosynthesis of cycloartenol and parkeol are discussed. 5. The (3)H/(14)C ratio for 24-methylenecycloartanol was 6:6, demonstrating that the hydrogen atom at C-24 is retained during alkylation of the cycloartenol side chain.

Carbon Isotopes↗
PubMed1990

3-Hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured fibroblasts from patients with mevalonate kinase deficiency: differential response to lipid supplied by fetal bovine serum in tissue culture medium.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity was measured in extracts of cultured fibroblasts derived from patients with mevalonate kinase deficiency (MKD). For six patients studied, the mean activity of 63.3 +/- 41.1 pmol/min-mg protein (+/- 1 SD, range 37.7-146.2) was significantly higher than the mean value in three control fibroblast lines of 11.1 +/- 3.5 (+/- 1 SD, range 8.0-14.9). These values were obtained using cells subcultured in medium supplemented with 10% fetal bovine serum (FBS) 21 h prior to assay. When cells were deprived of cholesterol by subculturing for 21 h in delipidated FBS, the mean value for patient cells was increased to 230.8 +/- 78.5 pmol/min-mg protein (range 130.9-333.8) as compared to 109.5 +/- 47.1 (range 78.0-163.6) for controls. The activity of HMG-CoA synthase in extracts of fibroblasts derived from the patients was not elevated. The mevalonic acid concentration in the surrounding culture medium was assessed by stable isotope dilution assay. For five patients, the mean concentration in medium containing FBS was 0.92 +/- 0.37 microM (+/- 1 SD, range 0.46-1.48) in contrast to 1.24 +/- 0.83 microM (range 0.46-2.54) for cells subcultured in delipidated FBS. The mean value for three control fibroblast lines was 0.22 +/- 0.12 microM (+/- 1 SD, range 0.11-0.35) for cells subcultured in FBS as compared to 0.01 +/- 0.01 microM (range 0.0-0.01 microM) for cells sucultured in delipidated FBS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in obesity: a stable isotope study.

1. We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable-isotope gas chromatography-mass spectrometry method in six obese subjects [three males, three females, age 41.5 +/- 3.4 years (mean +/- SEM), weight 105.0 +/- 4.8 kg, plasma total cholesterol concentration 6.2 +/- 0.4 mmol/l, triacylglycerol 2.8 +/- 0.8 mmol/l, high-density lipoprotein cholesterol 1.0 +/- 0.2 mmol/l] and six lean control subjects (three males, three females, age 41.8 +/- 3.7 years, weight 68.2 +/- 4.9 kg, total cholesterol concentration 4.5 +/- 0.3 mmol/l, triacylglycerol 0.8 +/- 0.2 mmol/l, high-density lipoprotein cholesterol 1.3 +/- 0.1 mmol/l). 2. Plasma total cholesterol, triacylglycerol and mevalonic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the obese subjects than in control subjects (P = 0.02, P = 0.03, P = 0.04, respectively). VLDL apoB pool size and absolute secretion rate were significantly higher in the obese subjects than in control subjects (323.4 +/- 99.8 mg versus 53.6 +/- 17.1 mg, P = 0.004; and 42.3 +/- 13.8 mg kg fat-free mass-1 day-1 versus 10.7 +/- 0.4 mg kg fat-free mass-1 day-1, P = 0.01), but there was no significant difference in the fractional catabolic rate of VLDL apoB.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1967

Turnover of plasma esterified cholesterol in normocholesterolemic and hypercholesterolemic subjects and its relation to body build.

The turnover rate of plasma total esterified cholesterol was measured after the intravenous injection of tritiated mevalonic acid in 16 men with coronary heart disease. Four subjects were normocholesterolemic and 12 were hypercholesterolemic; among the latter, 3 suffered from familial hypercholesterolemia and 6 were overweight. The turnover rate of plasma esterified cholesterol was highest among the overweight hypercholesterolemic subjects and least among the subjects with familial hypercholesterolemia. Hypercholesterolemic subjects of normal weight had turnover rates similar to those found in normocholesterolemic men. Significant correlations were found between body surface or body weight and the turnover rate of plasma esterified cholesterol. We conclude that the factors which determine the development of hypercholesterolemia are not identical in all hypercholesterolemic subjects and that when hypercholesterolemia is associated with overweight there is an increased formation of at least plasma esterified cholesterol.

Adult↗
PubMed1970

Biosynthesis of N-(alpha-hydroxyethyl) lysergamide, a metabolite of Claviceps paspali Stevens and Hall.

1. The biosynthetic origin of the amide substituent of N-(alpha-hydroxyethyl)lysergamide has been studied. 2. [1-(14)C]Acetate, [(14)C]formate, [2-(14)C]mevalonic acid lactone, [2-(14)C]indole, dl-[3-(14)C]tryptophan, dl-[3-(14)C]serine, dl-[2-(14)C]alanine and [2-(14)C]pyruvate were efficiently incorporated into the alkaloid, but not dl-[1-(14)C]alanine or [1-(14)C]pyruvate. 3. Only the dl-[2-(14)C]alanine- and [2-(14)C]pyruvate-derived alkaloid contained appreciable radioactivity in the amide substituent. 4. l-[(15)N]Alanine-derived alkaloid was shown to be specifically labelled in the amide nitrogen. However, l-[(14)C,(15)N]alanine was found to be incorporated into the methylcarbinolamide substituent with an appreciable increase in the (15)N/(14)C ratio, suggesting that alanine is not the direct precursor of this moiety.

Acetates↗
PubMed1997

[Pharmacological control of biosynthesis pathway of mevalonate: effect on the proliferation of arterial smooth muscle cells].

The role of mevalonic acid (MVA) and its products (isoprenoids) in cell proliferation prompted us to investigate the effect of drugs affecting diverse enzymatic steps of the MVA pathway on rat aorta smooth muscle cell (SMC) proliferation. Competitive inhibitors of HMG-CoA reductase (statins) decreased SMC proliferation in a dose-dependent manner. The inhibitory effect induced by simvastatin 3.5 microM (70% +/- 3.8 decrease) was prevented by addition of 100 microM MVA, (100% +/- 2.3), 10 microM farnesol (F-OH) (85% +/- 1.2) and 5 microM of all-trans geranylgeraniol (GG-OH) (precursor of prenylated proteins) (81% +/- 1.1), but not by 2-cis GG-OH (precursor of dolichols), squalene and ubiquinone. The same inhibitory effect was obtained with 6-fluoromevalonate (1-50 microM), an inhibitor of MVA-PP decarboxylase. Squalestatin 1 (1-25 microM) and NB-598 (1-10 microM), potent squalene synthase and epoxidase inhibitors, respectively, caused a complete inhibition of cholesterol synthesis without affecting SMC proliferation. Finally, BZA-5B (10-50 microM) a specific inhibitor of protein farnesyl tranferase (PFTase), inhibited SMC proliferation in a dose- (10-50 microM) and time-dependent manner, reaching 52% +/- 6.3 inhibition after 9 days, in the presence of 50 microM BZA-5B, without affecting cholesterol synthesis. This effect was partially prevented by mevalonate (76% +/- 3.2) and GG-OH (87% +/- 7.3) but not by F-OH. On the other hand, SMC proliferation was not affected by the closely related compound BZA-7B (93% +/- 4), which does not inhibit PFTase. Taken together, these findings support the involvement of specific isoprenoid metabolites, probably through farnesylated and geranylgeranylated proteins in cell proliferation.

Animals↗
PubMed1998

Apolipoprotein E genotype and cholesterogenesis in polygenic hypercholesterolemia.

We studied 22 normal-weight patients with polygenic hypercholesterolemia (PH), of which 11 (two males and nine females) had the apolipoprotein (apo) E3/4 genotype and 11 (one male and 10 females) the E3/3 genotype. The two groups were comparable for age, body mass index, total and low-density lipoprotein (LDL) cholesterol levels. The diagnosis of PH was made on the basis of clinical assessment, the criteria being type IIa hypercholesterolemia without tendon xanthomas and/or family history and clinical criteria indicative of familial hypercholesterolemia and/or familial combined hyperlipidemia. To avoid the influence of the habitual individual diet on cholesterogenesis, daily urinary mevalonic acid (MVA) excretion, an index of whole-body cholesterol synthesis, was evaluated in the steady-state condition while patients were on a low-fat, low-cholesterol diet for at least 3 months. Urinary MVA excretion rates were 2.52 +/- 0.8 micromol/24 h in E3/4 patients, significantly higher (P < .001) than in E3/3 patients (1.38 +/- 0.6 micromol/24 h). This is the first evidence of a higher rate of cholesterogenesis in PH patients carrying the epsilon4 allele versus the epsilon3 allele under a standardized lipid-lowering diet. We conclude that the higher rate of cholesterogenesis in PH patients with the epsilon4 allele might partly explain the interindividual differences in response to treatment with cholesterol synthesis inhibitors such as statins.

Alleles↗