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PubMed1995

Direct correlation between cholesterol synthesis and hepatic secretion of apolipoprotein B-100 in normolipidemic subjects.

The regulation of apolipoprotein B-100 (apo B) metabolism in man is not fully understood. In vitro studies suggest a key role for the hepatic availability of cholesterol substrate. We therefore examined whether there was a direct association between plasma mevalonic acid (MVA) concentration (an index of in vivo cholesterol synthesis) and hepatic secretion of very-low-density lipoprotein (VLDL) apo B in eight normolipidemic, healthy adult subjects. Hepatic secretion of VLDL apo B was estimated by endogenous labeling of apo B with an 8-hour primed, constant infusion of 1-13C-leucine. Isotopic enrichment of VLDL apo B was measured by gas chromatography-mass spectrometry (GCMS), from which the fractional secretion rate (FSR) was derived by a modified monoexponential function. Plasma concentration of MVA was measured by gas chromatography-electron-capture mass spectrometry in blood samples taken at 9 AM. The absolute secretion rate (ASR) of VLDL apo B (mean +/- SD) was 9.7 +/- 2.6 mg/kg/d, and MVA concentration was 5.0 +/- 2.5 ng/mL. There was a highly significant positive correlation between ASR of VLDL apoB and plasma MVA (r = .88, P = .004), which persisted after adjusting for apo E phenotype. The findings suggest that in vivo cholesterol synthesis is a determinant of hepatic secretion of apo B in normolipidemic subjects.

Adult↗
PubMed2003

Distinct light-mediated pathways regulate the biosynthesis and exchange of isoprenoid precursors during Arabidopsis seedling development.

Plants synthesize an astonishing diversity of isoprenoids, some of which play essential roles in photosynthesis, respiration, and the regulation of growth and development. Two independent pathways for the biosynthesis of isoprenoid precursors coexist within the plant cell: the cytosolic mevalonic acid (MVA) pathway and the plastidial methylerythritol phosphate (MEP) pathway. In at least some plants (including Arabidopsis), common precursors are exchanged between the cytosol and the plastid. However, little is known about the signals that coordinate their biosynthesis and exchange. To identify such signals, we arrested seedling development by specifically blocking the MVA pathway with mevinolin (MEV) or the MEP pathway with fosmidomycin (FSM) and searched for MEV-resistant Arabidopsis mutants that also could survive in the presence of FSM. Here, we show that one such mutant, rim1, is a new phyB allele (phyB-m1). Although the MEV-resistant phenotype of mutant seedlings is caused by the upregulation of MVA synthesis, its resistance to FSM most likely is the result of an enhanced intake of MVA-derived isoprenoid precursors by the plastid. The analysis of other light-hyposensitive mutants showed that distinct light perception and signal transduction pathways regulate these two differential mechanisms for resistance, providing evidence for a coordinated regulation of the activity of the MVA pathway and the crosstalk between cell compartments for isoprenoid biosynthesis during the first stages of seedling development.

Alleles↗
PubMed1976

The transport of esterified cholesterol in plasma high density lipoproteins of human subjects: a mathematical model.

The pattern of labeling of free and esterified cholesterol in the plasma high-density lipoproteins after an intravenous injection of [3H]-mevalonic acid has been examined in six human subjects with a variety of plasma lipoprotein phenotypes. Attempts have been made to fit these data to theoretical models of high-density lipoprotein esterified cholesterol transport constructed on the basis of previous experimental observation. The first model, which assumed that the high-density lipoprotein esterified cholesterol transport constructed on the basis of previous experimental observation. The first model, which assumed that the high-density lipoprotein esterified cholesterol comprised a single homogeneous pool, was incompatible with the observed data. The second model assumed a two-pool model in which all of the plasma esterified cholesterol was produced in a small, rapidly turning over subfraction of the high-density lipoproteins. From this pool it was assumed that esterified cholesterol was transferred to other lipoprotein fractions, including transfer to a larger and much more slowly turning over subfraction of the high density lipoproteins. The second model was quite compatible with the observed data. Furthermore, the calculated net transport of esterified cholesterol through the fast turning over pool was in a range similar to that reported elsewhere for whole plasma. It has been concluded that the two-pool model not only fits the experimental data, but also accords well with previously documented observations of plasma esterified cholesterol transport.

Adult↗
PubMed2004

Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans.

Our aim was to identify and quantify the major in vivo pathways of lipoprotein cholesteryl ester transport in humans. Normal (n = 7), bile fistula (n = 5), and familial hypercholesterolemia (FH; n = 1) subjects were studied. Each received isotopic free cholesterol in HDL, LDL, or particulate form, along with another isotope of free or esterified cholesterol or mevalonic acid. VLDL, intermediate density lipoprotein (IDL), LDL, HDL, blood cells, and bile were collected for up to 6 days for analysis of radioactivity and mass of free and esterified cholesterol. These raw data were subjected to compartmental analysis using the SAAM program. Results in all groups corroborated net transport of free cholesterol to the liver from HDL, shown previously in fistula subjects. New findings revealed that 70% of ester was produced from free cholesterol in HDL and 30% from free cholesterol in LDL, IDL, and VLDL. No evidence was found for tissue-produced ester in plasma. There was net transfer of cholesteryl ester to VLDL and IDL from HDL and considerable exchange between LDL and HDL. Irreversible ester output was from VLDL, IDL, and LDL, but very little was from HDL, suggesting that selective and holoparticle uptakes of HDL ester are minor pathways in humans. It follows that 1) they contribute little to reverse transport, 2) very high HDL would not result from defects thereof, and 3) the clinical benefit of high HDL is likely explained by other mechanisms. Reverse transport in the subjects with bile fistula and FH was facilitated by ester output to the liver from VLDL plus IDL.

Adult↗
PubMed2003

Cross-talk between the cytosolic mevalonate and the plastidial methylerythritol phosphate pathways in tobacco bright yellow-2 cells.

In plants, two pathways are utilized for the synthesis of isopentenyl diphosphate, the universal precursor for isoprenoid biosynthesis. The key enzyme of the cytoplasmic mevalonic acid (MVA) pathway is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). Treatment of Tobacco Bright Yellow-2 (TBY-2) cells by the HMGR-specific inhibitor mevinolin led to growth reduction and induction of apparent HMGR activity, in parallel to an increase in protein representing two HMGR isozymes. Maximum induction was observed at 24 h. 1-Deoxy-d-xylulose (DX), the dephosphorylated first precursor of the plastidial 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway, complemented growth inhibition by mevinolin in the low millimolar concentration range. Furthermore, DX partially re-established feedback repression of mevinolin-induced HMGR activity. Incorporation studies with [1,1,1,4-2H4]DX showed that sterols, normally derived from MVA, in the presence of mevinolin are synthesized via the MEP pathway. Fosmidomycin, an inhibitor of 1-deoxy-d-xylulose-5-phosphate reductoisomerase, the second enzyme of the MEP pathway, was utilized to study the reverse complementation. Growth inhibition by fosmidomycin of TBY-2 cells could be partially overcome by MVA. Chemical complementation was further substantiated by incorporation of [2-13C]MVA into plastoquinone, representative of plastidial isoprenoids. Best rates of incorporation of exogenous stably labeled precursors were observed in the presence of both inhibitors, thereby avoiding internal isotope dilution.

Cytosol↗
PubMed1982

Multicompartmental analysis of cholesterol metabolism in man. Quantitative kinetic evaluation of precursor sources and turnover of high density lipoprotein cholesterol esters.

The purpose of this study is to delineate the immediate sources and fractional turnover of high density lipoprotein (HDL) esterified cholesterol in man. Various labeled preparations were administered in 11 experiments to six subjects who had either a complete bile fistula (maximally stimulated cholesterol metabolism) or an intact enterohepatic circulation. The administered tracers included [(3)H]mevalonic acid; [(14)C]cholesterol bound to albumin; low density lipoprotein (LDL) free [(3)H] or [(14)C]cholesterol; HDL free [(3)H] or [(14)C]cholesterol; HDL esterified [(3)H]cholesterol; and LDL esterified [(3)H]cholesterol. Blood samples were obtained at frequent intervals for up to 5 d after the administration of tracers. The mass and radioactivity in individual plasma lipoprotein (very low density lipoprotein [VLDL], HDL, and LDL) free and esterified cholesterol were determined. The data were subjected to multicompartmental analysis using the SAAM-27 computer program. The analysis revealed that plasma free cholesterol was not the only immediate source of either a single- or two-compartment HDL ester system. When LDL esters and plasma (HDL) free cholesterol were tested together as sources of one HDL ester compartment, data from all the experiments were readily fit. The fluxes arrived at with the final model indicated that only approximately 20% of the esterified cholesterol in HDL was newly synthesized from plasma (HDL) free cholesterol (2.36 mumol/min); the remaining 80% was from LDL ester (8.92 mumol/min). The presence of a bile fistula had no obvious effect on HDL esterified cholesterol metabolism. The rate of HDL cholesterol ester turnover was 3-12 times/d, indicating that the ester component of the HDL particle is in a very dynamic state.

Adult↗
PubMed1998

Use of cholesterol precursors to assess changes in cholesterol synthesis under non-steady-state conditions.

BACKGROUND: Quantification of plasma levels of an early and late intermediate on the cholesterol pathway, mevalonic acid (MVA) and lathosterol respectively, provides a useful method of estimating cholesterol synthesis in humans. The aim of this study was to assess further their roles as indices of cholesterol synthesis under non-steady-state conditions. METHODS: The short-term effects of pharmacological inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase on both variables were determined in four normolipidaemic subjects during and after treatment with simvastatin 20 mg daily. Plasma MVA was measured using gas chromatography-mass spectrometry, and lathosterol using gas chromatography. RESULTS: A single dose of 20 mg of simvastatin decreased plasma MVA after 2 h and decreased the lathosterol-cholesterol (L/C) ratio after 4 h. Treatment with simvastatin 20 mg daily for 9 days decreased both variables by approximately 50%, the nadir of plasma MVA occurring on the second day and of the L/C ratio on the fifth day, and resulted in a 39% reduction in low-density lipoprotein (LDL)-cholesterol. After discontinuing simvastatin, there were rebounds in plasma MVA and the L/C ratio to above basal levels but not in LDL cholesterol or apolipoprotein B (apoB), the latter continuing to decrease for a further 2 days. CONCLUSION: These results suggest that simvastatin rapidly down-regulates cholesterol synthesis, which is then up-regulated when the drug is withdrawn.

Acyl Coenzyme A↗
PubMed1991

Evidence for isopentenyladenine modification on a cell cycle-regulated protein.

We have prepared antibodies that recognize isopentenyladenosine (i6A), a modified nucleoside derived from mevalonic acid (MVA). In immunoblot assays, affinity-purified anti-i6 A antibodies specifically bound to a 26-kDa protein (i6A26) in Chinese hamster ovary cells. Anti-i6A recognition of i6A26 was blocked with i6A but not adenosine or isopentenol. Employing immunoblot analysis we have quantitated the level of i6A26 in cells expressing various rates of DNA synthesis. The cellular content of i6A26 was reduced 4-fold in quiescent cells cultured in the absence of serum. When serum-deprived cells were stimulated to enter the cell cycle, the amount of i6A26 increased in the cells during the G1 phase. However, when synchronized cells were stimulated with serum-containing medium in the presence of mevinolin (an inhibitor of cellular MVA synthesis), we observed impaired G1 expression of i6A26 and delayed onset of S phase DNA synthesis. Mevinolin addition to asynchronously growing cells resulted in low rates of cellular DNA synthesis and suppressed levels of i6A26 which were reversed by coincubation with MVA. The ability of MVA to restore DNA synthesis and the cellular content of i6A26 in mevinolin-treated cells showed similar MVA concentration and time dependences. Regenerating liver tissue also exhibited elevated levels of i6A26. Thus, the expression of i6A26 correlates with cellular proliferation and growth. We speculate that i6A26 contains isopentenyladenine moieties and mediates isoprenoid regulation of DNA synthesis. Isopentenyladenylated proteins may also function in cytokinin regulation of proliferation and differentiation in plants.

Adenine↗
PubMed1994

Lack of correlation between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and lovastatin resistance in nerve growth factor treated PC-12 cells.

1. The relationships among the mevalonic acid (MVA) forming enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (CoA) reductase, cell growth and differentiation, and the cytotoxic effects of the reductase inhibitor lovastatin were studied in PC-12 cells, exposed to growth factors. 2. When added individually, nerve growth factor (NGF), basic fibroblast growth factor, and epidermal growth factor induce an increase in HMG-CoA reductase activity in cells grown in serum-containing medium. In the presence of serum, the effect of NGF on HMG-CoA reductase is persistent. 3. Short-term serum starvation and long-term NGF treatment, in combination, have an additive effect, resulting in a high reductase activity. 4. Unlike serum and MVA, which downregulate levels of HMG-CoA reductase by accelerating its degradation, NGF upregulates reductase by slowing the rate of its degradation. This mechanism, however, appears to operate only in the presence of serum, as after prolonged growth with NGF in serum-free medium, cells have a low reductase activity. 5. PC-12 cells grown in the absence of NGF are highly sensitive to lovastatin (25 microM) and more than 70% of the cells die after 48 hr. NGF confers lovastatin resistance on cells grown in the presence or in the absence of serum (only 30-40% cell death after 48 hr with lovastatin). 6. NGF-induced resistance on lovastatin develops with time and is apparent only in the well-differentiated PC-12 cells whether or not the cells express a high reductase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Acute and chronic effects on cholesterol biosynthesis of LDL-apheresis with or without concomitant HMG-CoA reductase inhibitor therapy.

To determine the acute and long-term effects of low density lipoprotein (LDL) reduction on cholesterol biosynthesis, we studied changes in the cholesterol precursors mevalonic acid (MVA) and lathosterol in patients with heterozygous familial hypercholesterolemia undergoing LDL-apheresis. Long-term LDL-apheresis in eight patients resulted in slight but insignificant increases in plasma MVA levels and lathosterol/cholesterol (L/C) ratios over 18 months. In short-term studies, six patients not on drugs and six patients treated with lovastatin or pravastatin had blood taken immediately before and after LDL-apheresis, and afterwards on days 1, 2, 3, 5, and 7. Plasma L/C ratios and MVA concentration did not change significantly on the first day after LDL-apheresis in those not on statin therapy (1.11 +/- 0.08 vs. 1.40 +/- 0.18, and 9.2 +/- 1.3 vs. 9.1 +/- 0.6 ng/ml, respectively) but increased in the statin-treated group (from 0.78 +/- 0.09 to 1.55 +/- 0.21, P = 0.003 and from 5.0 +/- 0.7 to 11.0 +/- 1.6 ng/ml, P = 0.008, respectively). There was no clear correlation between the changes in either of these precursors and the extent of reduction of total cholesterol by LDL-apheresis, but there was a strong inverse correlation with the post-apheresis LDL-cholesterol level (r = -0.77, P = 0.002 for L/C ratio; r = -0.75, P = 0.003 for MVA). Post-apheresis changes in L/C ratio and MVA were mutually correlated (r = 0.68. P = 0.01). We conclude that LDL-apheresis stimulates cholesterol biosynthesis transiently despite concomitant therapy with an HMG-CoA reductase inhibitor, the degree of stimulation being inversely related to the level to which the LDL-cholesterol was reduced.

Adult↗
PubMed1998

Dolichol-like lipids with stimulatory effect on DNA synthesis: substrates for protein dolichylation?

Substantial evidence has suggested that a nonsterol product of mevalonic acid (MVA) is essential for the initiation of DNA synthesis in mammalian cells. Several possible isoprenoid candidates have been suggested, but the identity of this compound still remains unknown. In this study we have isolated and purified MVA products from SV40-transformed human fibroblasts and identified fractions with a growth-stimulatory effect. The cells were labelled with [14C]MVA in the presence of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. After lipid extraction, the [14C]MVA-labelled lipids were subjected to high performance liquid chromatography and size-exclusion chromatography, and the effect of the fractionated eluate on the DNA synthesis of arrested MVA-depleted target cells was tested. Thereby we found a fraction of [14C]MVA-labelled lipids with a substantial stimulatory effect on DNA synthesis. The chromatographic behavior suggested that the growth-stimulating fractions contained dolichol-20. This was confirmed by mass spectrometric analysis. Similar results were obtained when lipids from hepatocellular carcinoma cells and a sample from breast tumor were isolated and analyzed by the same procedure. The mechanisms by which these compounds induce DNA synthesis are unknown. Recent data obtained in our laboratory have provided evidence that dolichyl groups are covalently linked to tumor cell proteins, which implicates a new biological function for long-chain polyisoprenoid alcohols (Hjertman et al. [1997] FEBS Lett 416:235-238). In this study we demonstrate that tumor cells containing dolichol-like growth-stimulatory lipids also contained dolichylated proteins. This raises the question whether the growth-stimulatory dolichol-like lipids serve as substrates for the dolichylation reaction.

Cell Division↗
PubMed1984

Plasma mevalonate as a measure of cholesterol synthesis in man.

Measurement of mevalonic acid (MVA) concentrations in plasma or 24-h urine samples is shown to be useful in studies of the regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol synthesis. Plasma MVA concentrations, measured either at 7-9 a.m. after an overnight fast, or throughout the 24-h cycle, were compared with cholesterol synthesis rates that were measured by the sterol balance method: plasma MVA concentrations were directly related to the rate of whole body cholesterol synthesis (r = 0.972; p less than 0.001; n = 18) over a tenfold range of cholesterol synthesis rates. Moreover, hourly examination of MVA concentrations throughout the day demonstrated that interventions such as fasting or cholesterol feeding cause suppression of the postmidnight diurnal rise in plasma MVA concentrations, with little change in the base-line of the rhythm. Thus, the daily rise and fall of plasma MVA appears to reflect changes in tissues and organs, such as the liver and intestine, that are known to be most sensitive to regulation by fasting or by dietary cholesterol. The hypothesis that short-term regulation of HMG-CoA reductase in tissues is quickly reflected by corresponding variations in plasma MVA was tested by using a specific inhibitor of HMG-CoA reductase, mevinolin, to block MVA synthesis. Mevinolin caused a dose-dependent lowering of plasma MVA after a single dose; and in patients who received the drug twice a day for 4 wk, it decreased 24-h urinary MVA output. Significant lowering of plasma cholesterol was achieved through administration of mevinolin at doses that only moderately limit MVA production.

Cholesterol↗
PubMed1975

Effect of trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride and carbon monoxide on hepatic cholesterol biosynthesis from 4,4,-dimethyl sterols in vitro.

The drug trans-1,4-bis(2-chlorobenzylaminomethyl)cyclohexane dihydrochloride (AY-9944) almost completely inhibited the conversion of [2-14C] mevalonic acid, dihydro[14C]lanosterol, 4,4-dimethyl-5alpha-[2-3H2]cholesta-8,14-dien-3beta-ol and 4,4-dimethyl-5alpha-[2-3H2]cholest-8(14)-en-3beta-ol to 5alpha-cholest-7-en-3beta-ol and cholesterol by cell-free systems of rat liver. With the first three precursors, the inhibition was accompanied by an accumulation of radioactive 5alpha-cholesta-8,14-dien-3beta-ol, but this material could not be detected during inhibition of cholesterol biosynthesis from 4,4-dimethyl-5alpha-[2-3H2] cholest-8(14)-en-3beta-ol. Regardless of the nature of the precursor, trans-1,4-bis(2-chlorobenzylaminomethyl)cyclohexane dihydrochloride did not result in the accumulation of any delta5,7 sterols. Non-radioactive 5alpha-cholest-8(14)-en-3beta-ol inhibited the conversion of dihydro[14C]lanosterol to 4,4-dimethyl-5alpha-cholesta-8,14-dien-3beta-ol. Carbon monoxide resulted in a decrease in the rate of conversion of dihydro[14C]lanosterol to 4,4-dimethyl-5alpha-cholesta-8,14-dien-3beta-ol but had no effect on the rate of conversion of 4,4-dimethyl-5alpha-[2-3H2]cholesta-8,14-dien-3beta-ol to 5alpha-cholest-7-en-3beta-ol and cholesterol suggesting that cytochrome P-450 is involved neither in the oxidative removal of the 4-methyl groups nor in the oxidative introduction of the delta5 bond during cholesterol biosynthesis. In addition, the process of cholesterol and 5alpha-cholest-7-en-3beta-ol biosynthesis from 4,4-dimethyl-5alpha-[2-3H2]cholest-8(14)-en-3beta-ol was inhibited by carbon monoxide at a stage after the formation of 5alpha-cholest-8(14)-en-3beta-ol.

Animals↗
PubMed1985

Role of the kidneys in the metabolism of plasma mevalonate. Studies in humans and in rhesus monkeys.

Studies were carried out in humans and in rhesus monkeys to determine the role of the kidneys in the metabolism of circulating mevalonic acid (MVA). Following intravenous infusion of [14C]MVA and [3H]cholesterol, there was a rapid appearance of [14C]squalene in the kidneys that exhibited a significantly longer half-life than plasma or hepatic squalene. In man and in rhesus monkeys there was a rapid equilibration between newly synthesized cholesterol from MVA and exogenously administered cholesterol in all tissues except the kidneys, where the specific activity ratio of newly synthesized to exogenous cholesterol was significantly higher. Estimates of the quantitative metabolism of intravenously infused radiolabeled MVA in the monkey demonstrated that 23% was excreted in the urine, 67% metabolized to cholesterol (58% in nonrenal tissues and 9% in the kidneys), and 10% catabolized to CO2 and nonsteroid products. Measurements of MVA metabolism in anephric and uninephric patients demonstrate that, in the absence of renal uptake of MVA, exogenous and newly synthesized cholesterol achieve almost instantaneous equilibrium in the plasma; whereas in control subjects with normal renal function, this equilibration required at least 21 d for the two cholesterol decay curves to become parallel. These results suggest that the kidneys are solely responsible for the observed disequilibrium between newly synthesized and exogenous cholesterol; we suggest that this was due to the delayed release of newly synthesized cholesterol from the kidneys into the plasma compartment following intravenous infusion with radiolabeled MVA. The data document the importance of the kidneys in the metabolism of circulating MVA. However, calculation of the quantitative significance of this pathway in relation to whole body MVA metabolism indicates that renal metabolism of MVA accounts for approximately 0.1% of daily MVA turnover, and that alterations in this pathway due to any form of renal pathology would not result in significant changes in hepatic or whole body sterol synthesis rates. We urge caution in the use of radiolabeled MVA in long-term kinetic studies of sterol metabolism because our data show that the plasma compartment of MVA is not necessarily in isotopic equilibrium with tissue MVA.

Adult↗
PubMed1995

Lifibrol: a novel lipid-lowering drug for the therapy of hypercholesterolemia. Lifibrol Study Group.

OBJECTIVE: To determine the effects of lifibrol on serum lipids in adult patients with primary hypercholesterolemia. METHODS: These were two double-blind, randomized placebo-controlled studies. Each patient in each study had an 8-week dietary lead-in period on the American Heart Association Step I diet before administration of lifibrol or placebo. The first study consisted of active dosing of 4 weeks, and the second study had 12 weeks of active dosing. The setting for the study involved outpatients in private or university hospitals in the United States. All patients had primary hypercholesterolemia with low-density lipoprotein (LDL) cholesterol levels of > 160 mg/dl after the dietary lead-in period. There were 155 patients in the 4-week study and 336 patients in the 12-week study. In the first study, patients were randomly assigned to receive either 150, 300, 450, 600, or 900 mg lifibrol as a single daily dose for 4 weeks. In the second study, patients were randomized to receive either 150, 300, or 600 mg lifibrol for 12 weeks. Efficacy was determined by serial measurements of serum lipids either on a weekly or biweekly basis during each study. RESULTS: Compared with baseline, lifibrol reduced LDL cholesterol (> 40%, p < 0.0001) and apolipoprotein B (approximately 40%, p < 0.0001) by 4 weeks in both studies. After 6 weeks, high-density lipoprotein (HDL) cholesterol levels increased in the placebo and 150 and 300 mg lifibrol groups. In the 600 mg lifibrol group, triglycerides (approximately 25%, p < 0.001), lipoprotein (a) (approximately 30%, p < 0.001), and HDL cholesterol (approximately 5%, p < 0.002) decreased. Lifibrol reduced key sterol intermediates (e.g., lanosterol, lathosterol, beta-sitosterol, and campesterol) and increased serum bile acids, but it had no effect on urinary mevalonic acid excretion. The pharmacokinetics of lifibrol are independent of dose and are similar in men and women. Lifibrol was well tolerated. The most frequent medical event in both studies was skin rash. CONCLUSIONS: Lifibrol is a potent lipid-lowering drug in patients with hypercholesterolemia.

Adolescent↗
PubMed1982

Partial purification and properties of mevalonate kinase from neonatal chick liver.

Mevalonate kinase from neonatal chick liver has been partially purified by ammonium sulphate precipitation and Sephadex G100 and DEAE-cellulose fractionation. The kinetic characteristics agreed with the sequential mechanism suggested for the enzyme and provided apparent Km values of 0.01 mM for mevalonic acid and 0.25 mM for ATP. Partially purified mevalonate kinase from neonatal chick liver showed an absolute specificity for ATP. Mn2+ was a better activator than Mg2+ at low concentrations (0.1-1.0 mM). Higher Mn2+ concentrations produced a clear inhibition of mevalonate kinase. Likewise, addition of EDTA, with or without metal ions, clearly inhibited the enzymatic reaction.

Adenosine Triphosphate↗
PubMed1998

Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras.

Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of metabolic bone diseases. Although the molecular targets of bisphosphonates have not been identified, these compounds inhibit bone resorption by mechanisms that can lead to osteoclast apoptosis. Bisphosphonates also induce apoptosis in mouse J774 macrophages in vitro, probably by the same mechanisms that lead to osteoclast apoptosis. We have found that, in J774 macrophages, nitrogen-containing bisphosphonates (such as alendronate, ibandronate, and risedronate) inhibit post-translational modification (prenylation) of proteins, including the GTP-binding protein Ras, with farnesyl or geranylgeranyl isoprenoid groups. Clodronate did not inhibit protein prenylation. Mevastatin, an inhibitor of 3-hydroxy-3-methylglutatyl (HMG)-CoA reductase and hence the biosynthetic pathway required for the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, also caused apoptosis in J774 macrophages and murine osteoclasts in vitro. Furthermore, alendronate-induced apoptosis, like mevastatin-induced apoptosis, could be suppressed in J774 cells by the addition of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, while the effect of alendronate on osteoclast number and bone resorption in murine calvariae in vitro could be overcome by the addition of mevalonic acid. These observations suggest that nitrogen-containing bisphosphonate drugs cause apoptosis following inhibition of post-translational prenylation of proteins such as Ras. It is likely that these potent antiresorptive bisphosphonates also inhibit bone resorption by preventing protein prenylation in osteoclasts and that enzymes of the mevalonate pathway or prenyl protein transferases are the molecular targets of the nitrogen-containing bisphosphonates. Furthermore, the data support the view that clodronate acts by a different mechanism.

Alendronate↗
PubMed1981

Further studies on mevalonate phosphorylation in neonatal chick brain.

Mevalonate phosphorylation was studied in neonatal chick brain. Formation of phosphorylated derivatives of mevalonic acid increased with the pH in the range assays (5.5-9.5). Phosphomevalonate kinase was completely inactivated after treatment at 50 degree C for 5-10 min, whereas mevalonate kinase was found to retain its activity under the same conditions. Exposure to 65 degree C for 5 min resulted in the inactivation of mevalonate kinase. Both mevalonate-activating enzymes from chick brain were located primarily in the soluble fraction. The amounts of phosphomevalonic acid and pyrophosphomevalonic acid did not show a significant diurnal variation to suggest the presence of a circadian rhythm in either kinase. Cholesterol feeding and fasting had no effect on mevalonate phosphorylation by neonatal chick brain.

Animals↗