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PubMed2001

Lovastatin induces apoptosis of spontaneously immortalized rat brain neuroblasts: involvement of nonsterol isoprenoid biosynthesis inhibition.

We have examined the effects of lovastatin and pravastatin (competitive HMG-CoA reductase inhibitors) on the growth and survival of rat brain neuroblasts. Lovastatin, but not pravastatin, suppressed cell growth by inducing apoptosis of neuroblasts in a dose- and time-dependent manner. Apoptosis was accompanied by a decrease in both Bcl-2 and Bcl-xL protein levels, suggesting that changes in the expression of these genes may contribute to apoptosis following lovastatin treatment. Lovastatin treatment was also associated with decreased prenylation of both Ras and Rho A proteins whereas Rac 1 geranylgeranylation was not affected. Lovastatin effects were fully prevented by mevalonate. The present data suggest that lovastatin induces apoptosis of rat brain neuroblasts by its capacity to decrease the prenylation of specific proteins involved in signal transduction pathways that control growth and survival of neuronal cells.

Animals↗
PubMed1985

Specific inhibition of fungal sterol biosynthesis by SF 86-327, a new allylamine antimycotic agent.

SF 86-327 is a new antimycotic agent of the allylamine type. Its primary action appears to be the inhibition of ergosterol biosynthesis at the point of squalene epoxidation, as was previously found with the related compound naftifine. Biosynthesis was measured by incorporation of [14C]acetate into sterols in cells of Candida albicans, Candida parapsilosis, Torulopsis glabrata, and the dermatophyte Trichophyton mentagrophytes. There was a positive correlation between the SF 86-327 concentrations needed for inhibition of growth and of sterol synthesis in these four fungi. The greater antifungal efficacy of SF 86-327 in comparison with naftifine was also reflected in the relative activities of the two compounds as sterol synthesis inhibitors. Inhibition was maximal at neutral pH. A similar degree of inhibition was found in cell-free extracts when [14C]mevalonate was used as substrate. In all cases, inhibition of sterol synthesis was accompanied by a parallel accumulation of labeled squalene. SF 86-327 and naftifine had no significant effect on initial enzymes of the ergosterol pathway, measured by incorporation of [14C]acetyl coenzyme A, or on steps distal to squalene epoxidation, measured by conversion of labeled squalene 2,3-epoxide or lanosterol. Both allylamines were highly selective for fungal, as opposed to mammalian, sterol biosynthesis. SF 86-327 caused slight inhibition of squalene epoxidation in a rat liver cell-free system, but at concentrations three to four orders of magnitude greater than those required for inhibition of the fungal pathway.

Allylamine↗
PubMed1996

Pravastatin affects blood pressure and vascular reactivity.

To investigate the effect of endogenous cholesterol synthesis on blood pressure and vascular response, a HMG CoA reductase inhibitor, pravastatin (1 or 10 mg/kg per day) was administered orally for 2 or 4 weeks to spontaneously hypertensive rats (SHR/lzm) and normotensive Wistar-Kyoto (WKY/lzm) rats. Blood pressure was significantly increased in the pravastatin-treated groups of both strains, occurring in WKY after a longer treatment period than in SHR. The thoracic aortas from SHR and WKY were pretreated with pravastatin (10(-4)M). The vascular response to norepinephrine in terms of both contractility and sensitivity, was increased in the pravastatin-treated SHR aorta but not in the WKY aorta. The increased response was not observed in the presence of mevalonate. Acetylcholine-induced vascular relaxation in the aortas from both strains was not affected by pravastatin pretreatment. These results suggest that the vascular response to norepinephrine may be affected by the intracellular cholesterol synthesis pathway.

Animals↗
PubMed1981

Biosynthesis of 3-hydroxy-3-methylglutaryl-CoA, 3-hydroxy-3-ethylglutaryl-CoA, mevalonate and homomevalonate by insect corpus allatum and mammalian hepatic tissues.

Both radioactively labeled 3-hydroxy-3-methyglutarylcoenzyme A and its homolog 3-hydroxy-3-ethylglutarylcoenzyme A are produced by a cytosolic fraction obtained from corpora allata-corpora cardiaca complexes of the moth Manduca sexta, incubated with [1-14C]acetylcoenzyme A plus unlabeled propionylcoenzyme A. A particulate fraction isolated from the same tissue was able to reduce [Me-3H]hydroxymethylglutaryl-CoA and [3-14C]hydroxyethylglutaryl-CoA to mevalonate and homomevalonate, respectively, when NADPH was used as the electron donor. These reactions are in keeping with the proposed homoisoprenoid biosynthetic pathway for certain of the insect juvenile hormones. Measurement of products produced in picomole levels was accomplished by their conversion to ultraviolet absorbing derivatives which were subsequently analyzed by thin-layer chromatography and liquid chromatography followed by collection and liquid scintillation counting of appropriate fractions. Similar assays conducted with cell-free preparations from corpora allata of the grasshopper Schistocerca nitens, the mealworm beetle Tenebrio molitor, and from rat liver, species in which homoisoprenoid compounds have not been detected, also resulted in formation of the normal and homologous products (although no hydroxymethylglutaryl-CoA/hydroxyethylglutaryl-CoA reductase activity could be demonstrated in T. molitor). The latter results indicate a rather loose substrate specificity of the enzymes leading to mevalonate formation.

Acyl Coenzyme A↗
PubMed1978

Evidence from cell-free systems for differences in the sterol biosynthetic pathway of Rhizoctonia solani and Phytophthora cinnamomi.

Cell-free preparations of both Rhizoctonia solani, a sterol-synthesizing fungus, and Phytophthora cinnamomi, a non-sterol-synthesizing fungus, incubated in the presence of [2(-14)C]mevalonate and iodacetamide, converted the mevalonate into labelled mevalonate 5-phosphate, mevalonate 5-pyrophosphate and isopentenyl pyrophosphate. In the absence of iodoacetamide, but under anaerobic conditions, the same preparations converted the mevalonate into labelled geraniol, farnesol and squalene, the first two compounds presumably as their pyrophosphates. When cell-free preparations of both organisms were incubated aerobically in the presence of [1(-14)C]isopentenyl pyrophosphate, only labelled geraniol, farnesol and squalene were recovered from the P. cinnamomi reaction mixture, whereas labelled geraniol, farnesol, squalene, squalene epoxide, lanosterol and ergosterol were present in the R. solani reaction mixture. When these same preparations were incubated in the presence of 14C-labelled squalene, labelled squalene epoxide, lanosterol and ergosterol were recovered from the R. solani reaction mixture. In contrast, the P. cinnamomi preparation was unable to convert the squalene into products further along the sterol pathway; instead, a portion of the labelled squalene was converted into water-soluble products, indicating the possible existence of a squalene-degradation process in this organism. It appears that the block in the sterol biosynthetic pathway of P. cinnamomi occurs at the level of squalene epoxidation.

Alkenes↗
PubMed1981

The effect of hydrocortisone on cholesterol metabolism of cultured human skin fibroblasts.

Hydrocortisone in physiologic concentrations resulted in a reduction in sterol synthesis by cultured normal human skin fibroblasts. These changes were observed when [14C]acetate, [14C]octanoic acid and 3H2O were used as precursors. However, the incorporation of [3H]mevalonic acid lactone into digitonin-precipitable sterols was not affected by hydrocortisone, suggesting that hydrocortisone inhibits sterol synthesis at a site prior to the formation of mevalonic acid. In contrast, the activity of hydroxymethylglutaryl-CoA reductase was stimulated several-fold by the hormone. Thus, the inhibitory effect of hydrocortisone on the cholesterol synthetic pathway may be on hydroxymethylglutaryl-CoA synthase.

Acetates↗
PubMed1986

Gibberellin metabolism in cell-free extracts from spinach leaves in relation to photoperiod.

Cell-free extracts capable of converting [(14)C]-labeled gibberellins (GAs) were prepared from spinach (Spinacia oleracea L.) leaves. [(14)C]-labeled GAs, prepared enzymically from [(14)C]mevalonic acid, were incubated with these extracts, and products were identified by gas chromatography-mass spectrometry. The following pathway was found to operate in extracts from spinach leaves grown under long day (LD) conditions: GA(12) --> GA(53) --> GA(44) --> GA(19) --> GA(20). The pH optima for the enzymic conversions of [(14)C]GA(53), [(14)C]GA(44) and [(14)C]GA(19) were approximately 7.0, 8.0, and 6.5, respectively. These three enzyme activities required Fe(2+), alpha-ketoglutarate and O(2) for activity, and ascorbate stimulated the conversion of [(14)C]GA(53) and [(14)C]GA(19). Extracts from plants given LD or short days (SD) were examined, and enzymic activities were measured as a function of exposure to LD, as well as to darkness following 8 LD. The results indicate that the activities of the enzymes oxidizing GA(53) and GA(19) are increased in LD and decreased in SD or darkness, but that the enzyme activity oxidizing GA(44) remains high irrespective of light or dark treatment. This photoperiodic control of enzyme activity is not due to the presence of an inhibitor in plants grown in SD. These observations offer an explanation for the higher GA(20) content of spinach plants in LD than in SD.

Journal Article↗
PubMed1999

The promoter of the rat 3-hydroxy-3-methylglutaryl coenzyme A reductase gene contains a tissue-specific estrogen-responsive region.

The isoprenoid metabolic pathway is mainly regulated at the level of conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to mevalonate, catalyzed by HMG CoA reductase. As estrogens are known to influence cholesterol metabolism, we have explored the potential regulation of the HMG CoA reductase gene promoter by estrogens. The promoter contains an estrogen-responsive element-like sequence at position -93 (termed Red-ERE), which differs from the ERE consensus by one mismatch in each half of the palindrome. A Red-ERE oligonucleotide specifically bound estrogen receptor in vitro and conferred receptor-dependent estrogen responsiveness to a heterologous promoter in all cell lines tested. However, expression of a reporter driven by the rat HMG CoA reductase promoter was induced by estrogen treatment after transient transfection into the breast cancer cell line MCF-7 cells but not in hepatic cell lines expressing estrogen receptor. Estrogen induction in MCF-7 cells was dependent on the Red-ERE and was strongly inhibited by the antiestrogen ICI 164,384. A functional cAMP-responsive element is located immediately upstream of the Red-ERE, but cAMP and estrogens inhibit each other in terms of transactivation of the promoter. Similarly, induction by estrogens was inhibited by micromolar concentrations of cholesterol, likely acting via changes in occupancy of the sterol-responsive element located 70 bp upstream of the Red-ERE. Thus, within its natural context, Red-ERE is able to mediate hormonal regulation of the HMG CoA reductase gene in tissues that respond to estrogens with enhanced cell proliferation, while it is not operative in liver cells. We postulate that this tissue-specific regulation of HMG CoA reductase by estrogens could partially explain the protective effect of estrogens against heart disease.

Animals↗
PubMed2000

Identification of peroxisomal targeting signals in cholesterol biosynthetic enzymes. AA-CoA thiolase, hmg-coa synthase, MPPD, and FPP synthase.

At least three different subcellular compartments, including peroxisomes, are involved in cholesterol synthesis. The peroxisomal targeting signals for phosphomevalonate kinase and isopentenyl diphosphate isomerase have been identified. In the current study we identify the peroxisomal targeting signals required for four other enzymes of the cholesterol biosynthetic pathway: acetoacetyl-CoA (AA-CoA) thiolase, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase, mevalonate diphosphate decarboxylase (MPPD), and farnesyl diphosphate (FPP) synthase. Data are presented that demonstrate that mitochondrial AA-CoA thiolase contains both a mitochondrial targeting signal at the amino terminus and a peroxisomal targeting signal (PTS-1) at the carboxy terminus. We also analyze a new variation of PTS-2 sequences required to target HMG-CoA synthase and MPPD to peroxisomes. In addition, we show that FPP synthase import into peroxisomes is dependent on the PTS-2 receptor and identify at the amino terminus of the protein a 20-amino acid region that is required for the peroxisomal localization of the enzyme. These data provide further support for the conclusion that peroxisomes play a critical role in cholesterol biosynthesis.

Acetyl-CoA C-Acetyltransferase↗
PubMed1998

Control of Rab5 and Rab7 expression by the isoprenoid pathway.

Rab proteins are small molecular mass GTP-ases involved in the regulation of vescicular transport. The ability of rab proteins to carry out their role in intracellular membrane traffic requires the post-translational attachment to their C-terminus of a geranylgeranyl group, an isoprenoid lipid moiety derived from mevalonate. Here we report that depletion of intracellular mevalonate by lovastatin in FRTL-5 thyroid cells specifically resulted in a four-fold increase of Rab5 and Rab7 protein levels. This increase was reversed within 4 h upon addition of mevalonate. Similarly lovastatin also induced, at same extent, mRNA levels. Lovastatin effect was not common to other prenylated proteins. Moreover incubation with cycloheximide abolished the observed increase in lovastatin treated cells, suggesting that the effect is mediated by newly synthesized protein. These findings demonstrate that Rab5 and Rab7 expression are regulated by the isoprenoid pathway.

Animals↗
PubMed1999

Involvement of tyrosine phosphorylation in HMG-CoA reductase inhibitor-induced cell death in L6 myoblasts.

Our previous studies have shown that the HMG-CoA reductase (HCR) inhibitor (HCRI), simvastatin, causes myopathy in rabbits and kills L6 myoblasts. The present study was designed to elucidate the molecular mechanism of HCRI-induced cell death. We have demonstrated that simvastatin induces the tyrosine phosphorylation of several cellular proteins within 10 min. These phosphorylations were followed by apoptosis, as evidenced by the occurrence of internucleosomal DNA fragmentation and by morphological changes detected with Nomarski optics. Simvastatin-induced cell death was prevented by tyrosine kinase inhibitors. The MTT assay revealed that the addition of mevalonic acid into the culture medium partially inhibited simvastatin-induced cell death. Thus, these results suggested that protein tyrosine phosphorylation might play an important role in the intracellular signal transduction pathway mediating the HCRI-induced death of myoblasts.

Animals↗
PubMed2004

Germ cell migration in zebrafish is dependent on HMGCoA reductase activity and prenylation.

Hydroxymethylglutaryl coenzyme A reductase (HMGCoAR) is required for isoprenoid and cholesterol biosynthesis. In Drosophila, reduced HMGCoAR activity results in germ cell migration defects. We show that pharmacological HMGCoAR inhibition alters zebrafish development and germ cell migration. Embryos treated with atorvastatin (Lipitor) exhibited germ cell migration defects and mild morphologic abnormalities. The effects induced by atorvastatin were completely rescued by prior injection of mevalonate, the product of HMGCoAR activity, or the prenylation precursors farnesol and geranylgeraniol. In contrast, squalene, a cholesterol intermediate further down the pathway, failed to rescue statin-induced defects. Moreover, pharmacologic inhibition of geranylgeranyl transferase 1 (GGT1) protein prenylation activity also resulted in abnormal germ cell migration. Thus, our pharmacological inhibition-and-rescue approach provided detailed information about the elements of isoprenoid biosynthesis that contribute to germ cell migration. Together with data from Drosophila (Santos and Lehmann, this issue), our results highlight a conserved role for protein geranylgeranylation in this context.

Animals↗
PubMed1982

Interrelationships of ubiquinone and sterol syntheses in cultured cells of neural origin.

Ubiquinone synthesis has been studied in cultured C-6 glial and neuroblastoma cells by utilizing an inhibitor, 3-beta-(2-diethylaminoethoxy) androst-5-en-17-one hydrochloride (U18666A), of cholesterol biosynthesis. Exposure of C-6 glial cells to nanomolar quantities of U18666A caused a marked inhibition of total sterol synthesis from [14C]acetate or [3H]mevalonate within minutes. A 95% inhibition was apparent after a 3-h exposure to 200 ng/ml of U18666A. These observations, together with studies of the incorporation of radioactivity from the two precursors into cholesterol, desmosterol, lanosterol, and squalene, indicated that although the most sensitive site to inhibition by U18666A is desmosterol reduction to cholesterol, a major site of inhibition is demonstrable at a more proximal site, perhaps squalene synthetase. As a consequence of the latter inhibition, exposure of C-6 glial cells to U18666A caused a marked stimulation of incorporation of [14C]acetate or [3H]mevalonate into ubiquinone. Over a wide range of U18666A concentrations, the increase in ubiquinone synthesis was accompanied by an approximately similar decrease in total sterol synthesis. Whereas in the absence of U18666A only approximately 7% of the radioactivity incorporated from [3H]mevalonate into isoprenoid compounds was found in ubiquinone, in the presence of the drug approximately 90% of incorporated radioactivity was found in ubiquinone. The reciprocal effects of U18666A on ubiquinone and sterol syntheses were apparent also in the neuronal cells. THe data thus demonstrate a tight relationship between ubiquinone and sterol biosyntheses in cultured cells of neural origin. In such cells ubiquinone synthesis is exquisitely sensitive to the availability of isoprenoid precursors derived from the cholesterol biosynthetic pathway.

Acetates↗
PubMed1998

Regulatory role of microsomal 3-hydroxy-3-methylglutaryl-coenzyme A reductase for shikonin biosynthesis in Lithospermum erythrorhizon cell suspension cultures.

The carbon skeleton of the naphthoquinone pigment shikonin, which is produced in Lithospermum erythrorhizon Sieb. et Zucc. cell-suspension cultures, is partly derived from the isoprenoid biosynthetic pathway. The requirement of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR, EC 1.1.1.34), a key enzyme of the mevalonate route to isoprenoids, for shikonin synthesis was investigated. Conserved regions of sequences from plant HMGR genes were used to design polymerase chain reaction (PCR) primers for the cloning of a cDNA fragment from L. erythrorhizon. The resulting 443-bp clone was used as a probe for Northern analyses and hybridized to an mRNA of approx. 2.5 kb. Under shikonin-producing conditions, microsomal HMGR enzyme activity as well as mRNA level closely correlated with the accumulation of shikonin derivatives. White light, which inhibits shikonin formation, was shown to strongly suppress HMGR gene expression. The results presented here indicate that HMGR plays a significant role in the regulation of shikonin biosynthesis and that the control appears to act at the transcriptional level.

Acyl Coenzyme A↗
PubMed2005

Regulation of macrophage cholesterol efflux through hydroxymethylglutaryl-CoA reductase inhibition: a role for RhoA in ABCA1-mediated cholesterol efflux.

The cholesterol biosynthetic pathway produces numerous signaling molecules. Oxysterols through liver X receptor (LXR) activation regulate cholesterol efflux, whereas the non-sterol mevalonate metabolite, geranylgeranyl pyrophosphate (GGPP), was recently demonstrated to inhibit ABCA1 expression directly, through antagonism of LXR and indirectly through enhanced RhoA geranylgeranylation. We used HMG-CoA reductase inhibitors (statins) to test the hypothesis that reduced synthesis of mevalonate metabolites would enhance cholesterol efflux and attenuate foam cell formation. Preincubation of THP-1 macrophages with atorvastatin, dose dependently (1-10 microm) stimulated cholesterol efflux to apolipoprotein AI (apoAI, 10-60%, p < 0.05) and high density lipoprotein (HDL(3)) (2-50%, p < 0.05), despite a significant decrease in cholesterol synthesis (2-90%). Atorvastatin also increased ABCA1 and ABCG1 mRNA abundance (30 and 35%, p < 0.05). Addition of mevalonate, GGPP or farnesyl pyrophosphate completely blocked the statin-induced increase in ABCA1 expression and apoAI-mediated cholesterol efflux. A role for RhoA was established, because two inhibitors of Rho protein activity, a geranylgeranyl transferase inhibitor and C3 exoenzyme, increased cholesterol efflux to apoAI (20-35%, p < 0.05), and macrophage expression of dominant-negative RhoA enhanced cholesterol efflux to apoAI (20%, p < 0.05). In addition, atorvastatin increased the RhoA levels in the cytosol fraction and decreased the membrane localization of RhoA. Atorvastatin treatment activated peroxisome proliferator activated receptor gamma and increased LXR-mediated gene expression suggesting that atorvastatin induces cholesterol efflux through a molecular cascade involving inhibition of RhoA signaling, leading to increased peroxisome proliferator activated receptor gamma activity, enhanced LXR activation, increased ABCA1 expression, and cholesterol efflux. Finally, statin treatment inhibited cholesteryl ester accumulation in macrophages challenged with atherogenic hypertriglyceridemic very low density lipoproteins indicating that statins can regulate foam cell formation.

ATP Binding Cassette Transporter 1↗
PubMed1992

[Evaluation of the therapeutic efficacy of pravastatin in monothereapy and in association with gemfibrozil in hypercholesterolemia associated with moderate hyperglyceridemia].

Pravastatin is a new drug that inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the key enzyme in cholesterol synthesis. It prevents mevalonate synthesis, thus reducing cholesterol. Pravastatin also stimulates the expression of LDL receptors, leading to an activation of this specific pathway of LDL catabolism. Gemfibrozil is a fibrate drug. Although the mechanism of hypolipidemic action of fibrates is not conclusively elucidated, it seems to involve reduction of LDL cholesterol secondary to decreased VLDL production and increased VLDL catabolism. Therefore, it might be hypothesized that combination therapy with both agents could afford greater reduction of cholesterol levels as compared to pravastatin alone. This study compared the efficacy and safety of pravastatin in monotherapy or in combination with gemfibrozil in the treatment of primary hypercholesterolemia with moderate hypertriglyceridemia. Thirty-eight subjects (aged 57 +/- 15 years, 25 M and 13 F) with baseline cholesterol levels > 220 mg/dl, were included in the study. Serum triglyceride levels were greater than 170 mg/dl and lower than 250 mg/dl. All patients initially followed 4 weeks of hypolipidemic diet. The patients were there assigned to receive either 20 mg once a day of pravastatin alone (n 13) or 20 mg of pravastatin in association with 600 mg of gemfibrozil daily (n 11). Fourteen additional patient, treated with diet only, served as a control group. The treatment plan provided 18 months of active treatment with clinical and laboratory controls every month. Both groups of treated patients showed a reduction of total and LDL-cholesterol levels. The HDL-cholesterol levels increased significantly both with pravastatin and with gemfibrozil.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1980

In vivo exchange of cholesteryl esters from low density lipoproteins to high density lipoproteins.

Labelled cholesteryl esters were injected within low density lipoproteins (LDL) in four subjects. In all experiments, cholesteryl esters transferred to HDL initially, at the rate of about 3% per hour. Very low density lipoprotein cholesteryl esters became labelled later, possibly by transfer from HDL. The simultaneous labelling of HDL free cholesterol by a second isotope (injected within mevalonic acid) showed that the rapid labelling of HDL cholesteryl esters from LDL was substantially faster than that from the esterification of HDL free cholesterol. While this process does not show net transfer of cholesteryl esters from LDL to HDL it indicates a pathway for equilibration of cholesteryl esters among plasma lipoproteins.

Aged↗
PubMed1972

Biosynthesis of 5 -cholestan-3 -ol in cerebrotendinous xanthomatosis.

Cerebrotendinous Xanthomatosis is a rare, inherited disease characterized by an extraordinary accumulation of cholestanol in all tissues, xanthomatous deposits in the brain, lungs, and Achilles tendons, premature atherosclerosis, and low plasma cholesterol concentrations. In two patients with the disease, the biosynthesis of cholestanol was examined by different techniques. After cholesterol-4-(14)C was injected intravenously into one patient, cholestanol and cholesterol isolated from the bile on 3 different days over the ensuing week contained significant radioactivity. The specific radioactivity-time curves for cholesterol-(14)C and cholestanol-(14)C suggested a precursor product relationship and provided additional evidence for the transformation of cholesterol into cholestanol. The second patient received intravenously a mixture of mevalonate-2-(14)C and stereospecifically labeled mevalonate-3R,4R-(3)H. Again cholesterol and cholestanol were isolated from the bile, and the (3)H/(14)C ratio in both sterols was almost the same. This experiment again demonstrated that the biosynthetic path of cholestanol proceeded through cholesterol and not directly from earlier 5alpha-H-saturated precursors. These two independent lines of evidence indicate that the extraordinary deposition of cholestanol in Cerebrotendinous Xanthomatosis arises from cholesterol presumably through the accentuation of the normal biosynthetic pathway.

Adult↗