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PubMed2000

Topical mevalonic acid stimulates de novo cholesterol synthesis and epidermal permeability barrier homeostasis in aged mice.

Extracellular lipids of the stratum corneum, which are composed of cholesterol, fatty acid, and ceramides, are essential for the epidermal permeability barrier function. With damage to the barrier, a decreased capacity for epidermal lipid biosynthesis in aged epidermis results in an impaired repair response. Mevalonic acid is an intermediate after the rate-limiting step in cholesterol biosynthesis, which is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase. In the present study, we investigated the effect of topical mevalonic acid on the murine epidermal permeability barrier function, comparing it with that of cholesterol. Topical treatment with acetone caused linear increases in transepidermal water loss, in proportion to the number of treatments more rapidly in aged mice than in young mice. Administration of mevalonic acid on aged murine epidermis enhanced its resistance against damage and the recovery rate of barrier function from acute barrier disruption. In contrast, although cholesterol also had the same effect, it required a much higher amount than mevalonic acid. In young mice, neither mevalonic acid nor cholesterol had any effect on resistance against acetone damage nor the recovery rate from acetone damage. In the skin of mice topically administered with mevalonic acid, stimulation of cholesterol synthesis and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity were both observed, whereas none was seen with stimulation by equimolar cholesterol. These data indicate that a topical application of mevalonic acid enhances barrier recovery in aged mice, which is accompanied by not only acceleration of cholesterol synthesis from mevalonic acid but also stimulation of the whole cholesterol biosynthesis.

Administration, Topical↗
PubMed1983

Cholesterol and mevalonic acid are independent requirements for the in vitro proliferation of human bone marrow granulocyte progenitor cells: studies using ML-236B.

ML-236B is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the key regulatory enzyme in the sequence that catalyzes the conversion of acetate to mevalonic acid in cholesterol biosynthesis. This compound caused marked inhibition of human bone marrow granulocyte progenitor cell (CFU-C) proliferation, the 50% inhibitory concentration (IHD50) being 2.0 X 10(6)M. Inhibition of colony formation was reversed by mevalonic acid but not by cholesterol. ML-236B also inhibited DNA synthesis and acetate incorporation into cholesterol in marrow mononuclear cells (IHD50 = 5.6 x 10(6)M and 3.2 x 10(7)M, respectively). No inhibition of mevalonate incorporation into cholesterol was observed. These results differ from those observed with 25-hydroxycholesterol, another inhibitor of HMG CoA reductase. The latter compound also inhibited CFU-C proliferation and cholesterol biosynthesis from acetate; inhibition of colony formation was reversed by cholesterol but not by mevalonic acid. In addition, 25-hydroxycholesterol inhibited cholesterol synthesis from mevalonic acid precursor. We conclude that: (1) ML-236B is a potent inhibitor of CFU-C proliferation, DNA synthesis, and cholesterol biosynthesis from acetate precursor in marrow mononuclear cells; (2) the effects of ML-236B are completely reversed by mevalonic acid but not by cholesterol, suggesting that mevalonic acid per se or one or more of its nonsterol products are critical for cell growth; (3) the inhibitory effects of 25-hydroxycholesterol on CFU-C proliferation and cholesterol biosynthesis are not solely a result of its inhibition of HMG CoA reductase, but are due in part to inhibition of enzymatic steps distal to mevalonic acid in the sterol synthetic pathway; and (4) mevalonic acid and cholesterol are independent requirements for CFU-C proliferation and differentiation in vitro.

Acetates↗
PubMed1965

COMPARATIVE BIOSYNTHESIS OF MEVALONIC ACID BY MYCOPLASMA.

Smith, Paul F. (University of South Dakota, Vermillion), and C. V. Henrikson. Comparative biosynthesis of mevalonic acid by Mycoplasma. J. Bacteriol. 89:146-153. 1965.-Three representative Mycoplasma, M. laidlawii strain B, M. gallisepticum strain J, and M. hominis strain 07, were examined for the presence or absence of enzymes associated with the biosynthetic pathway to mevalonic acid. M. laidlawii served as a control, because it synthesizes carotenoids from acetate. M. laidlawii was shown to contain a specific acetokinase and phosphotransacetylase for the synthesis of acetyl coenzyme A, and a beta-ketothiolase and coenzyme A transferase for the synthesis of acetoacetyl coenzyme A. M. gallisepticum contained a specific acetokinase, phosphotransacetylase, and possibly an aceto coenzyme A kinase forming acetyl coenzyme A; it also contained a beta-ketothiolase, a coenzyme A transferase, and a coenzyme A transphorase forming acetoacetyl coenzyme A directly or indirectly. The beta-ketothiolase of M. gallisepticum was not affected by iodoacetamide, in contrast to the other two strains. M. laidlawii exhibited beta-hydroxy-beta-methylglutaryl coenzyme A condensing enzyme, and M. hominis did not. This activity of M. gallisepticum was masked by thiolase activity. M. laidlawii and M. gallisepticum contained a nicotinamide adenine dinucleotide phosphate-linked beta-hydroxy-beta-methylglutaryl coenzyme A reductase, and M. hominis did not. C(14)-labeled acetate was incorporated into mevalonic acid only by M. laidlawii and M. gallisepticum. The lack of beta-hydroxy-beta-methylglutaryl coenzyme A condensing enzyme and reductase activities in M. hominis explains its growth requirement for sterol. The enzymatic block in M. gallisepticum must occur after mevalonic acid in the biosynthetic pathway to terpenoids.

Acetates↗
PubMed1991

Facts and artefacts in mevalonic aciduria: development of a stable isotope dilution GCMS assay for mevalonic acid and its application to physiological fluids, tissue samples, prenatal diagnosis and carrier detection.

A stable isotope dilution assay using D3-mevalonic acid was developed and applied to the study of mevalonic aciduria. The method also appears to be suitable for the evaluation of different therapeutic regimens in patients with hypercholesterolemia. Mevalonic acid was isolated by liquid partition chromatography and quantified as the underivatized lactone by means of ammonia chemical ionization selected ion monitoring capillary gas chromatography-mass spectrometry. In heterozygotes there was significantly greater urinary excretion of mevalonic acid, while the range of enzymatic activity of mevalonate kinase showed an overlap with that of controls. The analysis of amniotic fluids of two pregnancies at risk for mevalonic aciduria showed a 3277-fold elevation as compared to controls in the first case, diagnostic of an affected fetus, and a normal value in the second one. Mevalonic acid concentration was much increased in tissues of the affected and aborted fetus. Concentrations ranged from 840 to 1120 mumol/kg in various tissues and were as high as 1810 mumol/kg in brain. Concentrations in control fetal tissues were approximately 1 mumol/kg.

Adult↗
PubMed1973

Effect of Light on Mevalonic Acid Incorporation into the Phytosterols of Nicotiana tabacum L. Seedlings.

Mevalonic acid-2-(14)C was readily incorporated into the free, esterified, and glycosidic sterol fractions of tobacco (Nicotiana tabacum L. var. Burley 21) seedlings. The time course of mevalonic acid-2-(14)C incorporation was different for the various individual sterols. Campesterol and sitosterol (group I) became radioactive as the free sterol and subsequently as the steryl ester. The reverse order was observed for cholesterol and stigmasterol (group II). Light stimulated the incorporation of mevalonic acid-2-(14)C into the group I free sterols and during the first 6 to 9 hours into the steryl esters of group II. The increase in specific radioactivity of the group II steryl esters was followed by a decline. Based on time course studies it is suggested that the group II steryl esters turn over rapidly and that light influences the rate of turnover.

Journal Article↗
PubMed1989

Increased urinary mevalonic acid excretion in patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia.

Previous reports in which cholesterol homeostasis has been examined in patients with phenotypic abetalipoproteinemia have shown an increase in whole body cholesterol synthesis when measured by sterol balance techniques but normal rates of cholesterol synthesis when measured by isotopic cholesterol turnover. Recent studies have indicated that increases in cholesterol biosynthesis are paralleled by increases in the plasma concentrations of mevalonic acid and by higher rates of excretion of mevalonic acid in the urine. In the present report we have measured the 24-h urinary excretion of mevalonic acid in 7 patients with phenotypic abetalipoproteinemia and compared this to control subjects. Urinary excretion of mevalonic acid was significantly higher in the patients with abetalipoproteinemia (57.2 +/- 10.2 nmol/kg body weight per day, mean +/- SEM) as compared to control subjects (23.1 +/- 1.5 nmol/kg per day). The magnitude of the increase in urinary mevalonic acid excretion seen in patients with abetalipoproteinemia (148%) is greater than the increase in whole body cholesterol biosynthesis assessed by sterol balance techniques (57% increase). Our results serve to further validate the usefulness of urinary mevalonate as an indicator of relative rates of cholesterol biosynthesis in humans and suggest that this measurement provides a valuable means to potentially screen for disorders associated with an oversynthesis of cholesterol.

Abetalipoproteinemia↗
PubMed1967

Mevalonic acid kinase in Euglena gracilis.

The isolation and partial purification of mevalonic acid kinase from Euglena gracilis is described. The product of the reaction MVA-5-P has been characterized by paper chromatography. The apparent Km values for l-mevalonic acid, ATP, and Mg(2+) are 3 x 10(-5)m, 6 x 10(-3)m, and 9 x 10(-3)m, respectively. A concentration of 1 x 10(-3)mp-hydroxymercuribenzoate completely inactivates the enzyme. A distribution study has shown that mevalonic acid kinase is present in most higher plants and the algae Euglena gracilis and Chlamydomonas. No enzymatic activity could be detected in several species of photosynthetic bacteria or blue-green algae.

Adenosine Triphosphate↗
PubMed1987

[Formation of mevalonic acid, sterols and bile acids from [1-14C]acetyl-CoA and [2-14C]malonyl-CoA in the liver of rabbits with experimental hypercholesterolemia].

The effect of cholesterol diet on the rate of mevalonic acid biosynthesis from 1-14C acetyl-CoA, 2-14C malonyl-CoA and the incorporation of these substrates into sterols and bile acids in rabbit liver were studied. Simultaneously, the activities of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and acetyl-CoA carboxylase and the biosynthesis of fatty acids from acetyl-CoA and malonyl-CoA were measured. Hypercholesterolemia was found to be concomitant with the inhibition of acetyl-CoA carboxylase activity only in cell-free (700 g) and mitochondrial fractions and slightly decreased the incorporation of acetyl-CoA and malonyl-CoA into fatty acids in the postmitochondrial fraction. The HMG-CoA reductase activity in all subcellular fractions except for the postmicrosomal one was inhibited under these conditions. A significant decrease of acetyl-CoA incorporation and an increase in malonyl-CoA incorporation into mevalonic acid in all liver fractions except for microsomal one were observed in rabbits with hypercholesterolemia. These data provide evidence for the existence of two pathways of mevalonic acid synthesis from the above-said substrates that are differently sensitive to cholesterol. Cholesterol feeding resulted in a decreased synthesis of the total unsaponified fraction including cholesterol from acetyl-CoA, malonyl-CoA and mevalonic acid. The rate of incorporation of these substrates into lanosterol was unchanged. All the indicated substrates (acetyl-CoA, malonyl-CoA, mevalonic acid) are precursors of bile acid synthesis in rabbit liver. Cholesterol feeding and the subsequent development of hypercholesterolemia resulted in bile acid synthesis stimulation, preferentially in the formation of the cholic + deoxycholic acids from these precursors.

Acetyl Coenzyme A↗
PubMed1966

Conversion of mevalonic acid to gamma, gamma-dimethylallyl pyrophosphate by Mycoplasma.

Henrikson, Carl V. (University of South Dakota, Vermillion), and Paul F. Smith. Conversion of mevalonic acid to gamma,gamma-dimethylallyl pyrophosphate by Mycoplasma. J. Bacteriol. 92:701-706. 1966.-Three representative strains of Mycoplasma, M. laidlawii strain B, Mycoplasma sp. avian strain J, and M. hominis type 2 strain O7, were examined for the presence or absence of enzymes associated with the biosynthetic pathway from mevalonic acid to gamma,gamma-dimethylallyl pyrophosphate. M. laidlawii served as a control organism, since it is capable of de novo biosynthesis of carotenoids. All four enzymes, namely, adenosine triphosphate (ATP)-mevalonate 5-phosphotransferase (EC 2.7.1.36), ATP-5-phosphomevalonate phosphotransferase (EC 2.7.4.2), ATP-5-pyrophosphomevalonate carboxy-lyase (EC 4.1.1.33), and isopentenylpyrophosphate Delta(3),Delta(2)-isomerase (EC 5.3.3.2), were demonstrated in this organism. Mycoplasma sp. avian strain J, which contains all enzymes necessary for the biosynthesis of mevalonic acid, lacks the first three of the above enzymes but contains isopentenyl pyrophosphate Delta(3),Delta(2)-isomerase. M. hominis, which lacks the enzymes necessary for the biosynthesis of mevalonic acid, also is deficient in the enzymes involved in its conversion to gamma,gamma-dimethylallyl pyrophosphate.

Carbon Isotopes↗
PubMed1984

The DNA synthetic response of normal and abnormal human lymphocytes to mevalonic acid: the role of granulocytes as a helper population.

In order to investigate the role of neutrophils in the DNA synthetic response of human peripheral blood lymphocytes to mevalonic acid, we obtained preparations of both cells each free of cross-contamination by the other. Purified lymphocytes respond poorly to mevalonic acid, but their response can be significantly enhanced by one half their number of neutrophils. Preincubation of lymphocytes with neutrophils for 24 hr, even in the absence of mevalonic acid, further increases the lymphocyte response. We have been unable to demonstrate the production by granulocytes of either an intracellular or extracellular mevalonate-derived growth factor that in turn stimulates lymphocytes. Granulocytes preexposed to mevalonate do not acquire the ability to stimulate lymphocyte DNA synthesis in the absence of mevalonate. Our experiments suggest that neither neutrophil lysosomal enzymes nor reactive oxygen species generated by neutrophils are responsible for the help neutrophils provide. Normal E rosette-positive lymphocytes fail to respond to mevalonate, whereas E rosette-negative cells do. The mevalonate response of normal E rosette-negative cells is enhanced by the presence of granulocytes in contrast to B cell-chronic lymphocytic leukemia cells that synthesize DNA briskly in response to mevalonic acid in the absence of neutrophil help. These observations add to our knowledge of the relationship between mevalonate metabolism and the regulation of cellular DNA synthesis and mitosis.

Animals↗
PubMed1983

Synthesis of 3-hydroxy-3-cyclohexylbutyric acid derivatives. 2. Cyclic analogues of mevalonic acid.

The sodium salt of (Z)-3-hydroxy-3-(2-hydroxycyclohexyl)butyric acid (I) and its lactone (II) were prepared through the corresponding tert-butyl ester by hydrogenation, over Rh/Al2O3 catalyst, of the phenyl ring of tert-butyl 3-hydroxy-3-(2-hydroxyphenyl)butyrate (III). (Z)-3-Hydroxy-3-(2-methoxycyclohexyl)butyric acid was prepared similarly. (Z)-4-Methyloctahydro-2H-1-benzopyran-2-one was prepared by hydrogenation, over Rh/Al2O3 catalyst, of 4-methylcoumarine, prepared in turn from III by a one-pot procedure comprising hydrolysis, lactonization, and dehydration. The above compounds inhibit acetate incorporation in cholesterol and fatty acids in rat liver slices at 5 X 10(-3) M, but they lack specific inhibitory activity on HMG-CoA reductase.

Animals↗
PubMed1979

[Decarboxylation of malonyl-CoA and biosynthesis of mevalonic acid in rat liver].

Biosynthesis of mevalonic acid (MVA), total formation of 14CO2 from [1,3-14C]malonyl-CoA and the activity of malonyl-CoA decarboxylase in subcellular fractions of rat liver were studied. The dependence of the rate of MVA biosynthesis on malonyl-CoA concentration was found to be linear both in 140,000 g supernatant and solubilized microsomal fractions. It was shown that in a composite system (140,000 g supernatant fraction added to washed microsomes, 10 : 1) the optimal concentration ratio for the substrates of MVA biosynthesis (malonyl-CoA and acetyl-CoA) is 1 to 2. In the absence of acetyl-CoA decarboxylation of [1,3-14C]malonyl-CoA was prevalent. In all subcellular fractions studied decarboxylation of [1,3-14C]malonyl-CoA prevailed over its incorporation into MVA, total non-saponified lipid fraction and fatty acids. The degree of malonyl-CoA, decarboxylation was not correlated with the rate of its incorporation into MVA, i. e. the increase in the 14CO2 formation was not accompanied by stimulation of [1,3-14C]malonyl-CoA incorporation either into MVA or into total non-saponified lipid fractions. The incorporation of [1-14C]acetyl-CoA into MVA under the same conditions was considerably lower than that of [1,3-14C]malonyl-CoA. In all subcellular fractions under study the activity of malonyl-CoA decarboxylase was found. The experimental data suggest that a remarkable part of malonyl-CoA is incorporated into MVA without preliminary decarboxylation. A possible role of malonyl-CoA decarboxylase as an enzyme which protects the cell against accumulation of malonyl-CoA and its immediate metabolites -- malonate and methylmalonyl-CoA is disucssed.

Acyl Coenzyme A↗
PubMed1968

Production of mevalonic acid by fermentation.

The purpose of this investigation was to select microorganisms that produce substantial quantities of mevalonic acid and to develop an economic fermentation process. To screen for mevalonic acid-producing microorganisms, it was necessary to improve the method for the quantitative determination of this acid. The biological assay was modified by shortening the incubation time and simplifying the procedure. The principle of the assay is based on the essential mevalonic acid requirement of the organism Lactobacillus heterohiochii for growth. Screening was carried out by selecting high mevalonic acid-producing organisms from various type cultures. Endomycopsis fibuliger was chosen for medium development studies, and 939 mug of mevalonic acid per ml was produced in the culture filtrate after modifications of medium and fermentation conditions.

Aspergillus↗
PubMed1981

Mevalonic acid analogs as inhibitors of cholesterol biosynthesis.

A series of 20 mevalonic acid analogs was synthesized and tested for their ability to inhibit cholesterol biosynthesis from [2-14C]-mevalonate in rat liver homogenates. Removal of the 5-hydroxyl group from mevalonic acid produced an active inhibitor, 3-hydroxy-3-methylpentanoic acid. Removal of the 3-hydroxyl group, addition of an aromatic group in the 3-position, or insertion of a double bond reduced inhibitory activity. Compounds with an aromatic group or halide on the 5-position were active inhibitors. The most active inhibitor was 5-phenylpentanoic acid, with 50% inhibition at 0.064 mM.

Animals↗
PubMed1992

Correspondence between plasma mevalonic acid levels and deuterium uptake in measuring human cholesterol synthesis.

To assess the validity of two techniques capable of identifying immediate changes in human cholesterol production, plasma mevalonic acid levels and the rate of uptake of deuterium into plasma free cholesterol were compared in 5 healthy individuals over 48 h. The free-living subjects self-selected three meals per day prior to and during study. At t = 0, deuterium oxide was administered orally. Blood samples were collected before and every 4 h after dosing. Total cholesterol and mevalonic acid levels were determined in plasma at each timepoint. Deuterium enrichment changes in plasma free cholesterol, relative to plasma water content, were used to calculate free cholesterol fractional synthetic rates (FSR) at each timepoint. Total plasma cholesterol levels remained constant, whereas significant circadian rhythmicity was observed in both plasma mevalonic acid and deuterium uptake methods, with nadir and peak formation rates indicated at 14.00 to 16.00 h and about midnight, respectively. It is suggested that plasma mevalonic acid levels and free cholesterol deuterium uptake rate techniques are both suitable techniques for short-term measurement of human cholesterol synthesis.

Adult↗
PubMed1992

[The clinical evaluation of the hypocholesterolemic effects of an inhibitor of cholesterol synthesis: mevalonic acid].

Twenty eight patients with heterozygous familial hypercholesterolemia were treated with mevalonic acid (an inhibitor of cholesterol synthesis) for 45 days. Patients received a daily dose of 750 to 1500 mg mevalonic acid depending on plasma cholesterol levels. Results showed a significant reduction in cholesterol values whereas no significant difference was observed in HDL cholesterol and triglyceride levels.

Adult↗
PubMed1997

Effects of ubiquinone and mevalonic acid on hepatic peroxisomal enzymes induced by dehydroepiandrosterone.

The adrenal steroid, dehydroepiandrosterone (DHEA) has been identified as a peroxisome proliferator. We examined the effects of the cellular antioxidant ubiquinone and its precursor mevalonic acid on the induction of enzymes associated with DHEA-mediated peroxisome proliferation in male F-344 rats. Upon treatment with DHEA (300 mg/kg orally for 14 days), there was a significant increase in hepatic activities of peroxisomal beta-oxidation (3 fold), 3-ketoacyl-CoA thiolase (4 fold) and catalase (1.8 fold). Co-administration of either mevalonic acid (100 mg/kg intraperitoneally) or ubiquinone (50 mg/kg orally) with DHEA significantly attenuated the DHEA-mediated induction of these enzymes. However, neither ubiquinone nor mevalonic acid alone significantly altered peroxisomal enzyme activities in rat liver. These data suggest that exogenous administration of ubiquinone or mevalonic acid can modulate the induction of the enzymes involved in peroxisome proliferation.

Acetyl-CoA C-Acyltransferase↗