Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mevalonic Acid”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27Linked to original sources
PubMed1968

The role of bile salts in controlling the rate of intestinal cholesterogenesis.

According to current concepts, the liver and gastrointestinal tract are considered to be the major, if not the sole, sources of circulating serum cholesterol. While several mechanisms have been described which control the rate of hepatic cholesterogenesis, only biliary diversion is known to alter the rate of sterol synthesis in the intestine. The present study was designed to identify the inhibitory constituent of bile and to define its anatomic and biochemical sites of action. After either biliary diversion or cholestyramine feeding, there is a marked enhancement of cholesterogenesis at every level of the small intestine; this effect is specific for sterol synthesis since acetate incorporation into fatty acids and CO(2) is unaffected by these experimental manipulations. In the present investigation bile salt has been shown to be the constituent of whole bile responsible for the inhibited rate of sterol synthesis found in the intact animal, and in addition, an inverse relationship has been shown to exist between the steady-state intraluminal bile salt concentration and the rate of cholesterogenesis in the adjacent bowel wall. The inhibitory effect of bile salt is directed at the cells of the intestinal crypt, the major anatomic site for sterol synthesis in the small bowel. This feedback inhibition has been localized in the biosynthetic sequence to a step between acetyl CoA and mevalonic acid and, presumably, is at the enzymatic step mediated by hydroxymethylglutaryl reductase. These studies emphasize the close interrelationship which exists between the mechanisms of control of cholesterogenesis in the liver and small intestine. Sterol synthesis in the liver is regulated by exogenous cholesterol intake, whereas the rate of intestinal sterol synthesis is controlled by bile salt, the major end product of the hepatic catabolism of cholesterol.

Acetates↗
PubMed1979

Diminution of L cell microvilli following exposure to 25-hydroxycholesterol.

The effect of sterol depletion on the topology of mouse L cells was studied by scanning electron microscopy. Treatment of cells with 25-hydroxycholesterol inhibited the synthesis of cellular sterol and diminished the number of microvilli on the cell surface. Simultaneous addition of mevalonic acid or cholesterol to cells during treatment with the inhibitor prevented the loss of microvilli. These results demonstrate that cholesterol is important in maintaining the ultrastructure of the surface membrane of nucleated mammalian cells.

Cell Membrane↗
PubMed2000

Effect of inhibition of sterol delta 14-reductase on accumulation of meiosis-activating sterol and meiotic resumption in cumulus-enclosed mouse oocytes in vitro.

Two sterols of the cholesterol biosynthetic pathway induce resumption of meiosis in mouse oocytes in vitro. The sterols, termed meiosis-activating sterols (MAS), have been isolated from human follicular fluid (FF-MAS, 4,4-dimethyl-5 alpha-cholest-8,14,24-triene-3 beta-ol) and from bull testicular tissue (T-MAS, 4,4-dimethyl-5 alpha-cholest-8,24-diene-3 beta-ol). FF-MAS is the first intermediate in the cholesterol biosynthesis from lanosterol and is converted to T-MAS by sterol delta 14-reductase. An inhibitor of delta 7-reductase and delta 14 reductase, AY9944-A-7, causes cells with a constitutive cholesterol biosynthesis to accumulate FF-MAS and possibly other intermediates between lanosterol and cholesterol. The aim of the present study was to evaluate whether AY9944-A-7 added to cultures of cumulus-oocyte complexes (COC) from mice resulted in accumulation of MAS and meiotic maturation. AY9944-A-7 stimulated dose dependently (5-25 mumol l-1) COC to resume meiosis when cultured for 22 h in alpha minimal essential medium (alpha-MEM) containing 4 mmol hypoxanthine l-1, a natural inhibitor of meiotic maturation. In contrast, naked oocytes were not induced to resume meiosis by AY9944-A-7. When cumulus cells were separated from their oocytes and co-cultured, AY9944-A-7 did not affect resumption of meiosis, indicating that intact oocyte-cumulus cell connections are important for AY9944-A-7 to exert its effect on meiosis. Cultures of COC with 10 mumol AY9944-A-7 l-1 in the presence of [3H]mevalonic acid, a natural precursor for steroid synthesis, resulted in accumulation of labelled FF-MAS, which had an 11-fold greater amount of radioactivity incorporated per COC compared with the control culture without AY9944-A-7. In contrast, incorporation of radioactivity into the cholesterol fraction was reduced 30-fold in extracts from the same oocytes. The present findings demonstrate for the first time that COC can synthesize cholesterol from mevalonate and accumulate FF-MAS in the presence of AY9944-A-7. Furthermore, AY9944-A-7 stimulated meiotic maturation dose dependently, indicating that FF-MAS, and possibly other sterol intermediates of the cholesterol synthesis pathway, play a central role in stimulating mouse oocytes to resume meiosis. The results also indicate that oocytes may not synthesize steroids from mevalonate.

Animals↗
PubMed2005

Neonatal mortality from in utero exposure to perfluorooctanesulfonate (PFOS) in Sprague-Dawley rats: dose-response, and biochemical and pharamacokinetic parameters.

Perfluorooctanesulfonate (PFOS) is a widely distributed, environmentally persistent acid found at low levels in human, wildlife, and environmental media samples. Neonatal mortality has been observed following PFOS exposure in a two-generation reproduction study in rats and after dosing pregnant rats and mice during gestation. Objectives of the current study were to better define the dose-response curve for neonatal mortality in rat pups born to PFOS-exposed dams and to investigate biochemical and pharmacokinetic parameters potentially related to the etiology of effects observed in neonatal rat pups. In the current study, additional doses of 0.8, 1.0, 1.2, and 2.0 mg/kg/day were included with original doses used in the two-generation study of 0.4 and 1.6 mg/kg/day in order to obtain data in the critical range of the dose-response curve. Biochemical parameters investigated in dams and litters included: (1) serum lipids, glucose, mevalonic acid, and thyroid hormones; (2) milk cholesterol; and (3) liver lipids. Pharmacokinetic parameters investigated included the interrelationship of administered oral dose of PFOS to maternal body burden of PFOS and the transfer of maternal body burden to the fetus in utero and pup during lactation, as these factors may affect neonatal toxicity. Dosing of dams occurred for 6 weeks prior to mating with untreated breeder males, through confirmed mating, gestation, and day four of lactation. Dose levels for the dose-response and etiological investigation were 0.0, 0.4, 0.8, 1.0, 1.2, 1.6, and 2.0 mg/kg/day PFOS. Statistically significant decreases in gestation length were observed in the 0.8 mg/kg and higher dose groups. Decreases in viability through lactation day 5 were observed in the 0.8 mg/kg and higher dose groups, becoming statistically significant in the 1.6 and 2.0 mg/kg dose groups. Reduced neonatal survival did not appear to be the result of reductions in lipids, glucose utilization, or thyroid hormones. The endpoints of gestation length and decreased viability were positively correlated, suggesting that late-stage fetal development may be affected in pups exposed to PFOS in utero and may contribute to the observed mortality. Benchmark dose (BMD) estimates for decreased gestation length, birth weight, pup weight on lactation day 5, pup weight gain through lactation day 5, and viability resulted in values ranging from 0.27 to 0.89mg/kg/day for the lower 95% confidence limit of the BMD5 (BMDL5). Results of analyses for PFOS in biological matrices indicate a linear proportionality of mean serum PFOS concentration to maternal administered dose prior to mating and through the first two trimesters of gestation. However, at 21 days of gestation, mean serum PFOS concentrations were notably reduced from values measured earlier in gestation. Urinary and fecal elimination was low as expected from prior observations in adult rats. Significant transfer of PFOS from dam to fetus in utero was confirmed, and results suggest that dam and corresponding fetal body burdens, as indicated by serum and liver PFOS levels, correlate with neonatal survival.

Alkanesulfonic Acids↗
PubMed1991

Cell cycle-specific effects of lovastatin.

Lovastatin (LOV), the drug recently introduced to treat hypercholesteremia, inhibits the synthesis of mevalonic acid. The effects of LOV on the cell cycle progression of the human bladder carcinoma T24 cell line expressing activated p21ras were investigated. At a concentration of 2-10 microM, LOV arrested cells in G1 and also prolonged--or arrested a minor fraction of cells in--the G2 phase of the cell cycle; at a concentration of 50 microM, LOV was cytotoxic. The cytostatic effects were reversed by addition of exogenous mevalonate. Cells arrested in the cycle by LOV were viable for up to 72 hr and did not show any changes in RNA or protein content or chromatin condensation, which would be typical of either unbalanced growth or deep quiescence. The expression of the proliferation-associated nuclear proteins Ki-67 and p105 in these cells was reduced by up to 72% and 74%, respectively, compared with exponentially growing control cells. After removal of LOV, the cells resumed progression through the cycle; they entered S phase asynchronously after a lag of approximately 6 hr. Because mevalonate is essential for the posttranslational modification (isoprenylation) of p21ras, which in turn allows this protein to become attached to the cell membrane, the data suggest that the LOV-induced G1 arrest may be a consequence of the loss of the signal transduction capacity of p21ras. Indeed, while exposure of cells to LOV had no effect on the cellular content of p21ras (detected immunocytochemically), it altered the intracellular location of this protein, causing its dissociation from the cell membrane and translocation toward the cytoplasm and nucleus. However, it is also possible that inhibition of isoprenylation of proteins other than p21ras (e.g., nuclear lamins) by LOV may be responsible for the observed suppression of growth of T24 cells.

Cell Cycle↗
PubMed1991

Inhibition of protein isoprenylation and p21ras membrane association by dehydroepiandrosterone in human colonic adenocarcinoma cells in vitro.

Treatment of mice and rats with the adrenal steroid, dehydroepiandrosterone (DHEA), protects against spontaneous and chemically induced tumors. The mechanism of the chemopreventive action of DHEA, however, remains uncertain. DHEA has been reported to inhibit cholesterol biosynthesis. Mevalonic acid constitutes the basic precursor not only for cholesterol but also for a variety of nonsterol isoprenoids involved in cell growth. Certain of these nonsterol isoprenoids are utilized for posttranslational modification of proteins including p21ras. We therefore investigated the effects of DHEA upon protein isoprenylation. Twenty-four-h exposure of HT-29 SF human colonic adenocarcinoma cells to 50 microM DHEA was associated with significant incorporation of products of [3H]mevalonate metabolism into several size classes of cellular proteins. The pattern of incorporation was similar to that obtained after treatment with 25 microM lovastatin, a specific 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor. Very little incorporation of label from [3H]mevalonate was observed in untreated cells. This suggests that [3H]mevalonate gains entrance to isoprenylation sites after treatment with DHEA or lovastatin because of depletion of endogenous mevalonate and subsequent inhibition of protein isoprenylation. Isoprenylation plays a critical role in promoting the association of p21ras with the cell membrane. Posttranslational processing and membrane association of p21ras were both found to be inhibited by DHEA. Thus, it is possible that the inhibition of isoprenylation of p21ras and other cellular proteins by DHEA may contribute to its anti-cancer effects.

Adenocarcinoma↗
PubMed2002

Biosynthesis of sterols and triterpenes in cell suspension cultures of Uncaria tomentosa.

Pectin administered to Uncaria tomentosa cell suspension cultures, was found to increase the production of triterpene acids (ursolic and oleanolic acid), however, neither growth nor sterol accumulation were affected. Cell cultures showed that pectin treatment caused a rapid threefold increase in the activities of enzymes involved in the biosynthesis of C(5) and C(30 )isoprenoid, such as isopentenyl diphosphate isomerase and squalene synthase. The activity of a farnesyl diphosphatase, which could divert the flux of farnesyl diphosphate to farnesol, was two times lower in elicited than in control cells. Elicited cells also transformed more rapidly a higher percentage of [5-(3)H]mevalonic acid into triterpene acids. Interestingly, addition of terbinafine, an inhibitor of squalene epoxidase, to elicited cell cultures inhibited sterol accumulation while triterpene production was not inhibited. These results suggest that in U. tomentosa cells, both the previously mentioned enzymes and those involved in squalene 2,3-oxide formation play an important regulatory role in the biosynthesis of sterols and triterpenes.

Carbon-Carbon Double Bond Isomerases↗
PubMed1976

Non-human primate platelets and arterial tissue cannot convert preformed [14C]lanosterol into[14C]cholesterol in vivo.

In contrast with the prevailing view, we report the inability of non-human primate platelets or arterial tissue to complete the biosynthesis of [14C]cholesterol from [14C]mevalonic acid in vitro or in vivo, or from performed [14C]lanosterol in vivo. The latter observation suggests that these tissues lack one or more components of the methyl sterol demethylase system.

Animals↗
PubMed1996

Reduced cholesterol esterification in CaCo-2 cells by indirect action of pravastatin.

In microsomal preparations of CaCo-2 cells pravastatin decreased cholesterol esterifying activity at 25 micrograms/ml to 82.5% and at 800 micrograms/ml to 56.2% of controls. Pravastatin reduced cholesteryl ester formation dose-dependently also in viable CaCo-2 cells. However, the maximal inhibition was by 90.4% at pravastatin concentration of 25 micrograms/ml, half maximal inhibition occurred between concentrations of 5 and 10 micrograms/ml. Addition of mevalonolactone, which serves as endogenous source of cholesterol, antagonized this effect. At 10 mM mevalonolactone (MVL) even doses up to 200 micrograms/ml of pravastatin were ineffective. On the other hand, pravastatin suppressed cholesteryl ester formation when acyl-CoA cholesterol acyltransferase (ACAT) (E.C. 2.3.1.26) activity was stimulated by addition of exogenous liposomal or Low Density Lipoprotein (LDL)-derived cholesterol. This inhibition was refractory to increasing amounts of exogenous cholesterol up to 400 micrograms/ml. Therefore we conclude that only excessive doses of pravastatin suppress ACAT activity directly. In viable cells the observed inhibition of cholesteryl ester formation is due to the block in de novo synthesis of cholesterol, causing a lack of substrate for ACAT and of non-sterol products of mevalonic acid. Furthermore pravastatin interferes with the esterification and/or intracellular transport only of exogenous cholesterol, confirming former results of a compartmentalized cholesterol metabolism in the enterocyte.

Caco-2 Cells↗
PubMed1985

Mechanism of the inhibition of cholesterol biosynthesis by 6-fluoromevalonate.

6-Fluoromevalonate blocks the incorporation of mevalonic acid, but not that of isopentenyl pyrophosphate, into non-saponifiable lipids in a rat liver multienzyme system. With 3H-labelled 6-fluoromevalonate, it was found that 6-fluoromevalonate is converted to its phospho and pyrophospho derivatives in this system. The kinetics of the two kinases were studied. 6-Fluoromevalonate 5-pyrophosphate is a potent competitive inhibitor of pyrophosphomevalonate decarboxylase (Ki 37 nM). In the multienzyme assay for cholesterol biosynthesis, there is accumulation of mevalonate 5-phosphate and mevalonate 5-pyrophosphate in the presence of 5 microM-6-fluoromevalonate, and 6-fluoromevalonate 5-pyrophosphate is more effective than 6-fluoromevalonate in inhibiting cholesterol biosynthesis. We suggest therefore that 6-fluoromevalonate blocks cholesterol biosynthesis at the level of pyrophosphomevalonate decarboxylase after being pyrophosphorylated.

Animals↗
PubMed2005

Statin-inhibited endothelial permeability could be associated with its effect on PECAM-1 in endothelial cells.

UNLABELLED: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to inhibit leukocyte recruitment to endothelium but the mechanism is less understood. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an endothelial junction protein involved in leukocyte diapedesis. We hypothesize that in endothelial cells, statins may well recruit PECAM-1 to exert their inhibitory effect on leukocyte trans-endothelial migration (TEM). In lovastatin-treated resting human umbilical vein endothelial cells (HUVECs), increased levels of mRNA and protein of PECAM-1 as well as its bio-synthesis (all approximately 2-fold) were observed by real-time PCR, Western blotting and 35S-labeled methionine incorporation assay, respectively. Moreover, in lovastatin treated resting cells as well as TNF-alpha activated endothelial cells, unanimously decreased Triton X-100 insoluble and soluble PECAM-1 ratio was observed. Such changes were accompanied by decreased TEM of U-937 cells (a promonocyte cell line). All lovastatin's effects were abrogated by mevalonic acid. In resting HUVECs, geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP) (both are isoprenoid intermediates in the cholesterol biosynthesis pathway) compromised the effect of lovastatin on PECAM-1 expression, whereas C3 toxin, an inhibitor of small G proteins, exerted statin-like effect. CONCLUSION: Statin-reduced endothelial permeability could be attributed to altered intracellular distribution of PECAM-1 in endothelial cells. We speculate that lovastatin regulates PECAM-1 expression in HUVECs through the mevalonate-GGPP pathway by inhibiting of Rho small GTPase.

Cells, Cultured↗
PubMed1976

Kinetic analysis of the individual reductive steps catalyzed by beta-hydroxy-beta-methylglutaryl-coenzyme A reductase obtained from yeast.

The mechanism of action of yeast beta-hydroxy-beta-methylglutaryl-coenzyme A reductase has been investigated through kinetic studies on the oxidation of mevaldate by nicotinamide adeninine dinucleotide phosphate (NADP) in the presence of coenzyme A (CoA) and on the reduction of mevaldate by reduced NADP (NADPH) in the absence of presence of CoA or acetyl-CoA. NADP and mevalonate were also used as product inhibitors of the reduction of mevaldate. In the reduction of mevaldate to mevalonate, coenzyme A and acetyl-CoA decreased the Km for mevaldate 30- and 3-fold, respectively. Both compounds increased the Vmax 1.5-fold. These results suggest that CoA is an allosteric activator for the second reductive step and that it acts by enhancing the binding of mevaldate. The intersecting patterns obtained from initial velocities and the patterns produced by product inhibitions suggest the following features of the mechanism. The binding of substrates and release of products proceeds sequentially in both reductive steps, and is ordered throughout or random with respect to the binding of the beta-hydroxy-beta-methylglutaryl-coenzymeA and the first NADPH. The binding of NADPH enhances the binding of the beta-hydroxy-beta-methylglutaryl portion of the CoA ester and the binding of free mevaldate, whereas the binding of NADP leads to an increased affinity of the enzyme for the hemithioacetal (of mevaldate and CoA) and for mevalonate. Thus, the replacement of NADP by NADPH after the first reductive step promotes the conversion of the hemithioacetal to the free carbonyl form, which is then rapidly reduced. The products, CoA and mevalonic acid, of the second reductive step leave the enzyme before the release of the second NADP. This release of the last product is probably the rate-limiting step for the overall process.

Alcohol Oxidoreductases↗
PubMed1993

Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages.

Human monocyte-derived macrophages treated with increasing concentrations of the HMG-CoA reductase inhibitor, simvastatin, showed a dose-dependent decrease in superoxide formation in response to activation by phorbol myristate acetate. As a consequence, they oxidized LDL much less than untreated cells. Addition of exogenous mevalonic acid to simvastatin-treated macrophages restored their ability for superoxide production and for oxidative modification of LDL. These results indicate that simvastatin might prevent atherosclerosis by additional mechanisms besides its hypocholesterolemic activity.

Drug Interactions↗
PubMed1998

A sterol biosynthetic pathway in Mycobacterium.

The genome sequence of Mycobacterium tuberculosis (and also M. leprae) revealed a significant number of homologies to Saccharomyces cerevisiae sterol biosynthetic enzymes. We addressed the hypothesis of a potential sterol biosynthetic pathway existing in Mycobacterium using cultures of Mycobacterum smegmatis. Non-saponifiable lipid extracts subjected to analysis by gas chromatography-mass spectrometry (GC-MS) showed cholesterol was present. Sterol synthesis by M. smegmatis was confirmed using 14C-radiolabelled mevalonic acid and incorporation into C4-desmethyl sterol co-migrating with authentic cholesterol on TLC. The sterol biosynthetic pathway has provided a rich source of targets for commercially important bioactive molecules and such agents represent new opportunities for Mycobacteria chemotherapy.

Cholesterol↗
PubMed1994

Heat shock enhances the amount of prenylated Dnaj protein at membranes of glyoxysomes.

Proteins similar to the bacterial Dnaj protein have been implicated as molecular chaperones in different compartments of eukaryots. A plant equivalent is now described in tissues of dark-grown cucumber seedlings. Using a cucumber Dnaj protein produced by expression in bacteria, we raised polyclonal antibodies against the protein and used them for localization studies. In etiolated cucumber seedlings, both cotyledons and hypocotyledons were found to contain Dnaj proteins. Cell fractionation of etiolated cotyledons showed that Dnaj proteins were detectable mainly in the postnuclear cell fraction after sedimentation at 10,000 x g, and in the microsomes. Following subfractionation by sucrose density gradient centrifugation and analysis by immunoblotting, a 53-kDa protein was attributed to the glyoxysomal fraction and an 80-kDa protein to the mitochondrial fraction. The glyoxysomal Dnaj protein behaved as a membrane-bound form. Upon heat shock, a slight increase in the content of the glyoxysomal Dnaj protein was found. When glyoxysomes were treated with protease and subsequently isolated by gradient centrifugation, virtually all immunologically detectable Dnaj protein was removed. Administration of radiolabelled mevalonic acid to cotyledons and isolation of glyoxysomes yielded labelled Dnaj protein which remained membrane bound during the purification of glyoxysomal membranes by floatation in a density gradient.

Cell Fractionation↗
PubMed1981

Effect of oxygenated sterol compounds on human bone marrow granulocytic progenitor cells.

Oxygenated sterol compounds are potent inhibitors of sterol and DNA synthesis in mammalian cells. We studied the effects of oxygenated sterols on human marrow granulocytic progenitor cells in vitro (CFU-C). 25-Hydroxycholesterol was found to be a potent inhibitor of sterol synthesis in marrow mononuclear cells, with 50% inhibition occurring at approximately 10(-7) M. This compound, as well as 6-ketocholestanol, 7-ketocholesterol, and 20 alpha-hydroxycholesterol, also demonstrated marked inhibition of CFU-C proliferation. The latter effect, which was not a result of direct cytoxicity of the compounds, was reversible by cholesterol, but not by mevalonic acid. We conclude that inhibition of sterol synthesis by oxygenated sterol compounds may be insufficient to explain their suppression of CFU-C proliferation.

Bone Marrow↗
PubMed1973

Identification of prenol intermediates of wall biosynthesis in growing cells of Lactobacillus plantarum.

The incorporation of (14)C-mevalonic acid by Lactobacillus plantarum predominantly into C(55) prenol made it possible to determine the distribution of (14)C-prenol between all its derivatives. In logarithmic-phase cells, 25% of the prenol was free, 31% was as monophosphate, 4% as pyrophosphate, 12% as peptidoglycan precursor, and 28% as glyco-phospho-prenol. The glyco-phospho-prenol contained rhamnose, and probably glucose, galactose, and ribitol phosphate, and it may, therefore, be involved in polysaccharide and teichoic acid biosynthesis. The proportion of free prenol increased, up to 73%, as the cell culture aged. Free prenol was also formed when cells were incubated in buffer. The free prenol was readily reutilized when cells were returned to growth medium.

Carbohydrates↗