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PubMed2006

Hypertrophic cardiomyopathy, cataract, developmental delay, lactic acidosis: a novel subtype of 3-methylglutaconic aciduria.

3-Methylglutaconic aciduria is the biochemical marker of several inherited metabolic diseases. Four types of 3-methylglutaconic aciduria can be distinguished. In the type I form, accumulation of 3-methylglutaconate is due to deficient activity of 3-methylglutaconyl-CoA hydratase, an enzyme of the leucine degradation pathway. In the other forms, 3-methylglutaconic acid is not derived from leucine but is of unidentified origin, possibly derived from other metabolic pathways, such as mevalonate metabolism. We report five patients, all presenting a severe early-onset phenotype characterized by 3-methylglutaconic aciduria, hypertrophic cardiomyopathy, cataract, hypotonia/developmental delay, lactic acidosis, and normal 3-methylglutaconyl-CoA hydratase activity. This peculiar phenotype, for which a primary mitochondrial disorder is hypothesized, identifies a novel subtype of 3-methylglutaconic aciduria.

Acidosis, Lactic↗
PubMed2006

Cloning and characterization of a root-specific expressing gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase from Ginkgo biloba.

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR, EC: 1.1.1.34) catalyzes the first committed step in mevalonic acid (MVA) pathway for biosynthesis of isoprenoids. The full-length cDNA encoding HMGR was isolated from Ginkgo biloba for the first time (designated as GbHMGR, GenBank accession number AY741133), which contained a 1713 bp ORF encoding 571 amino acids. The GbHMGR genomic DNA sequence was also obtained, revealing GbHMGR had four exons and three introns. The deduced GbHMGR protein showed high identity to other plant HMGRs and contained two trans-membrane domains and a catalytic domain. The three dimensional model of GbHMGR represented a typical spatial structure of HMGRs. The Southern blot and RT-PCR assay results indicated that GbHMGR belonged to a small gene family, and expressed in a tissue-specific manner with a low level expression being only found in root. The potential significance of GbHMGR gene was also discussed.

Amino Acid Sequence↗
PubMed1979

Effect of milk constituents on hepatic cholesterol-genesis.

Two preparations active in reducing hepatic cholesterol biosynthesis were isolated from bovine skim milk. One of the inhibitors was in the dialysate and was identified as orotic acid (OA). The other inhibitor, present in the retentate, was not identified. Orotic acid appears to act by inhibiting cholesterol biosynthesis before the formation of mevalonate, whereas the retentate inhibitor exerts its effect beyond the formation of mevalonate in the biosynthetic pathway. Human milk also inhibited the incorporation of both labeled acetate and mevalonate into cholesterol by rat liver. Orotic acid was not detectable in human milk samples employed in this study. Administration of [6-14C]orotate to rats revealed its conversion to uracil in the liver. Subsequent work demonstrated that uracil had inhibitory activity on hepatic cholesterol biosynthesis similar to that of orotate when incubated with rat liver slices.

Acetates↗
PubMed2026

Postzygotic biallelic inactivation of FDFT1 underlies solitary lesion formation in porokeratosis of Mibelli.

BACKGROUND: Porokeratosis reflects clonal expansion of keratinocytes with biallelic inactivation of mevalonate-cholesterol biosynthesis pathway genes. In disseminated porokeratosis (DP), lesions arise through independent somatic second hits in carriers of heterozygous germline pathogenic variants, whereas porokeratosis of Mibelli (PM) is usually solitary, and its molecular basis remains incompletely defined. OBJECTIVE: To elucidate the molecular basis of solitary PM. METHODS: We analyzed blood and lesional epidermis from seven patients with solitary PM within a 156-patient porokeratosis cohort using deep sequencing, copy-number/SNP profiling, and methylation analysis. RESULTS: Solitary PM plaques were larger and more irregular than the annular DP lesions. No pathogenic germline variants were detected in MVK, PMVK, MVD, FDPS, or FDFT1. Three patients had somatic biallelic genetic inactivation of FDFT1 through putative deleterious variants and/or focal microdeletions. The remaining four showed FDFT1 promoter hypermethylation with loss of heterozygosity (LOH) at the FDFT1 locus due to copy-neutral LOH or a monoallelic 8p deletion, consistent with early monoallelic epigenetic silencing, followed by genetic loss of the remaining active allele. In one patient, part of the plaque expanded centrifugally over 7.5 years. CONCLUSION: Solitary PM can be driven by postzygotic, lesion-restricted, biallelic inactivation of FDFT1 through genetic or epigenetic mechanisms within a single epidermal clone, promoting clonal expansion. This model may explain the tendency toward solitary PM lesions. The low probability of acquiring postzygotic biallelic inactivation without germline predisposition may underlie solitary PM and suggest a low recurrence risk for offspring, unlike DP driven by germline heterozygosity.

General dermatology↗
PubMed2003

Identification of an allele of CLA1 associated with variegation in Arabidopsis thaliana.

We have identified a mutant of Arabidopsis thaliana (lvr111) that exhibits a variegated phenotype, reduced isoprenoid pigmentation, and dwarfism in comparison with wild-type plants. Segregation analysis indicated that this phenotype was caused by a single, semi-dominant mutation and PCR-based marker mapping placed the mutation near position 56 on the RI map of chromosome IV. The lvr111 lesion was identified by genomic PCR and sequence analysis as a missense mutation (D306N) in the CLA1 gene (AT4g15560) and complementation analysis confirmed the allelic relationship between lvr111 and CLA1. CLA1 encodes 1-deoxy-d-xylulose 5-phosphate synthase, which catalyses the first step of the non-mevalonate isoprenoid biosynthetic pathway. These observations demonstrate that, unlike the albinism caused by severe alleles of CLA1, weaker alleles are associated with leaf variegation.

Journal Article↗
PubMed1997

Activators of the nuclear hormone receptors PPARalpha and FXR accelerate the development of the fetal epidermal permeability barrier.

Members of the superfamily of nuclear hormone receptors which are obligate heterodimeric partners of the retinoid X receptor may be important in epidermal development. Here, we examined the effects of activators of the receptors for vitamin D3 and retinoids, and of the peroxisome proliferator activated receptors (PPARs) and the farnesoid X-activated receptor (FXR), on the development of the fetal epidermal barrier in vitro. Skin explants from gestational day 17 rats (term is 22 d) are unstratified and lack a stratum corneum (SC). After incubation in hormone-free media for 3-4 d, a multilayered SC replete with mature lamellar membranes in the interstices and a functionally competent barrier appear. 9-cis or all-trans retinoic acid, 1,25 dihydroxyvitamin D3, or the PPARgamma ligands prostaglandin J2 or troglitazone did not affect the development of barrier function or epidermal morphology. In contrast, activators of the PPARalpha, oleic acid, linoleic acid, and clofibrate, accelerated epidermal development, resulting in mature lamellar membranes, a multilayered SC, and a competent barrier after 2 d of incubation. The FXR activators, all-trans farnesol and juvenile hormone III, also accelerated epidermal barrier development. Activities of beta-glucocerebrosidase and steroid sulfatase, enzymes previously linked to barrier maturation, also increased after treatment with PPARalpha and FXR activators. In contrast, isoprenoids, such as nerolidol, cis-farnesol, or geranylgeraniol, or metabolites in the cholesterol pathway, such as mevalonate, squalene, or 25-hydroxycholesterol, did not alter barrier development. Finally, additive effects were observed in explants incubated with clofibrate and farnesol together in suboptimal concentrations which alone did not affect barrier development. These data indicate a putative physiologic role for PPARalpha and FXR in epidermal barrier development.

Animals↗
PubMed2003

Contribution of increased HMG-CoA reductase gene expression to hypercholesterolemia in experimental chronic renal failure.

The aim of the present study was to examine hypothesis that the enhanced cholesterologenesis, found in rats with experimental chronic renal failure (CRF) resulted from the increased gene expression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase--the rate limiting enzyme in the cholesterologenesis pathway, responsible for mevalonate synthesis. Wistar rats were used and experimental CRF was achieved by 5/6 nephrectomy model. We examined: (a) the changes in the rat liver microsomal HMG-CoA reductase activity, (b) the rat liver HMG-CoA reductase mRNA abundance in various times of day. Obtained data indicates that the increased activity of HMG-CoA reductase in the liver of rats with experimental CRF parallel enhanced mRNA level and suggests that enhanced cholesterol biosynthesis, observed in experimental CRF is at least in part due to the increased HMG-CoA reductase gene expression. The results also indicate that the physiological diurnal rhythm of HMG-CoA reductase activity is preserved in the course of experimental CRF.

Animals↗
PubMed2003

Production of rubber-like polymers by microorganisms.

Biopolymers with true rubber properties are exceptionally rare in prokaryotic microorganisms. Only some polyhydroxyalkanoic acids are thermoplastic elastomers within a narrow temperature range that can be extended by crosslinking. Other polyhydroxyalkanoic acids are rigid and need specific thermal treatment during annealing to yield elastomeric materials. The most important elastomer is natural rubber (cis-1,4-polyisoprene). The rubber tree Hevea brasiliensis is so far the only relevant commercial source of this polymer, although many other plants are also capable of its synthesis. Recent advances in the analysis of isoprenoid and polyisoprene biosynthesis pathways have encouraged attempts to establish production of natural rubber in bacteria. Establishment of functional cis-1,4-polyisoprene biosynthesis pathways in bacteria depends firstly on the biosynthesis of isoprene moieties via the mevalonate or methylerythritol phosphate pathway and secondly on the polymerisation of isoprene moieties by a prenyltransferase yielding high-molecular-weight polyisoprenoids. The genes that encode prenyltransferases are as yet unknown and so the establishment of such a pathway and formation of rubber in recombinant bacteria will be a difficult task.

Bacteria↗
PubMed1995

Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase by mevalonate.

We have examined the mechanisms of sterol-independent regulation of the expression of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase by mevalonate in Chinese hamster ovary (CHO) cells. Serum lipoproteins, 25-hydroxycholesterol, or mevalonate each repress HMG-CoA reductase activity by fivefold or more, and mevalonate lowers the rate of reductase synthesis by twofold. However, while the expression of the HMG-CoA reductase promoter construct, T42 delta CAT, in stable transfectants is also repressed by serum lipoproteins and 25-hydroxycholesterol, mevalonate is without effect. In addition, while 25-hydroxycholesterol reduces the steady-state level of endogenous HMG-CoA reductase mRNA by more than threefold, mevalonate again has no effect. Mevalonate does partially regulate the expression of both the artificial promoter construct pTK-Kx3-CAT, containing three copies of the sterol regulatory element, SRE-1, and the full-length LDL receptor promoter construct, pLDLRCAT-6500 as well as the expression of functional LDL receptors. This transcriptional regulation appears to be mediated by sterol end products generated from added mevalonate. In CHO cells starved for mevalonate due to a mutation in the biosynthetic pathway, addition of 20 mM mevalonate accelerates the rate of degradation of HMG-CoA reductase by threefold whether new sterol biosynthesis is blocked or not. In such cells, addition of 25-hydroxycholesterol, by itself, also decreases the half-life of reductase from 11.6 to 2.3 h. In contrast, in cells acutely treated with a reductase inhibitor, sterol-accelerated degradation of reductase is only observed in the presence of submillimolar level of mevalonate. We conclude that large concentrations of exogenous mevalonate fail to generate a transcriptional regulator of HMG-CoA reductase in CHO cells but do lead to the formation of translational regulator(s) of reductase synthesis. In contrast, sterol regulators derived from exogenous mevalonate appear to be capable of downregulating the LDL receptor promoter. We further conclude that in the absence of pretreatment with a reductase inhibitor, the regulatory signals generated by sterols and nonsterols for accelerated degradation of HMG-CoA reductase are mutually independent. However, the enzyme synthesized in the presence of reductase inhibitors appears to exhibit an obligatory corequirement for low-dose mevalonate for sterol-accelerated degradation.

Animals↗
PubMed2005

Isoprenoid biosynthesis in chloroplasts via the methylerythritol phosphate pathway: the (E)-4-hydroxy-3-methylbut-2-enyl diphosphate synthase (GcpE) from Arabidopsis thaliana is a [4Fe-4S] protein.

The mevalonate-independent methylerythritol phosphate pathway is widespread in bacteria. It is also present in the chloroplasts of all phototrophic organisms. Whereas the first steps, are rather well known, GcpE and LytB, the enzymes catalyzing the last two steps have been much less investigated. 2-C-Methyl-D-erythritol 2,4-cyclodiphosphate is transformed by GcpE into 4-hydroxy-3-methylbut-2-enyl diphosphate, which is converted by LytB into isopentenyl diphosphate or dimethylallyl diphosphate. Only the bacterial GcpE and LytB enzymes have been investigated to some extent, but nothing is known about the corresponding plant enzymes. In this contribution, the prosthetic group of GcpE from the plant Arabidopsis thaliana and the bacterium Escherichia coli has been fully characterized by Mossbauer spectroscopy after reconstitution with (57)FeCl(3), Na(2)S and dithiothreitol. It corresponds to a [4Fe-4S] cluster, suggesting that both plant and bacterial enzymes catalyze the reduction of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate into (E)-4-hydroxy-3-methylbut-2-enyl diphosphate via two consecutive one-electron transfers. In contrast to the bacterial enzyme, which utilizes NADPH/flavodoxin/flavodoxin reductase as a reducing shuttle system, the plant enzyme could not use this reduction system. Enzymatic activity was only detected in the presence of the 5-deazaflavin semiquinone radical.

Amino Acid Sequence↗
PubMed1974

Acceleration of hepatic sterol synthesis after a single dose of the porphyrogenic chemical allylisopropylacetamide.

Hepatic sterol synthesis is accelerated in animals after a single dose of allylisopropylacetamide, a chemical known to be porphyrogenic. Evidence is provided to show that enhanced sterol biosynthesis is due to an increased formation of mevalonic acid, indicating that the primary site of action of the chemical is on one or more steps in the pathway from acetate to mevalonate.

Acetamides↗
PubMed2001

Tracer studies on the incorporation of [2-14C]-DL-mevalonate into chlorophylls a and b, alpha-chaconine, and alpha-solanine of potato sprouts.

Chlorophyll and glycoalkaloids are synthesized in different parts of the potato plant including leaves, tubers, and sprouts. Although light stimulates the biosynthesis of both constituents, the question of whether the two biosynthetic pathways are under the same genetic control has not been resolved. This study investigated the dynamics of incorporation of labeled [2-(14)C]-DL-mavalonate into chlorophyll a, chlorophyll b, and the glycoalkaloids alpha-chaconine and alpha-solanine in potato sprouts after 7 and 14 days of storage in the light and in the dark. No chlorophyll synthesis occurred in the dark. Fractionation of the "glycoalkaloid" extract followed by high-performance liquid chromatography produced four peaks. The fractions were collected and analyzed for radioactivity. About 80% of the radioactivity resided in fraction 1, the composition of which is unknown. Two of the fractions, with 1-14% of the original label, were alpha-chaconine and alpha-solanine. The radioactivity derived from mevalonate largely resides in unidentified compound(s) eluting as a single peak on the HPLC column before the peaks associated with the glycoalkaloids. The specific radioactivity of alpha-chaconine and alpha-solanine increased approximately 2-fold in going from 7 to 14 days of exposure in the light and in the dark. These and additional observations point to the near identity of the dynamics of biosynthesis of the two glycoalkaloids. These data also implicate a non-mevalonate pathway for the synthesis of both chlorophylls and the glycoalkaloids and are consistent with independent genetic control of the concurrent formation of the two classes of compounds during greening of potatoes.

Carbon Radioisotopes↗
PubMed1982

Impaired renal mevalonate metabolism in nephrotic syndrome: a stimulus for increased hepatic cholesterogenesis independent of GFR and hypoalbuminemia.

Increased hepatic lipogenesis in the nephrotic syndrome is not adequately explained by hypoalbuminemia. In this disorder an enhanced delivery of the cholesterol precursor mevalonic acid (MVA) to the liver may be an unidentified stimulus to cholesterogenesis. Since the kidneys are the major site of mevalonate excretion and metabolism by either the sterol or nonsterol shunt pathways, an impairment of any of these metabolic alternatives could result in redistribution of mevalonate to the liver. Male Sprague-Dawley rats rendered nephrotic by puromycin aminonucleoside had their kidneys perfused with Krebs-Henseleit-bicarbonate buffer containing albumin, glucose and 5-14C-MVA. The number five carbon label was utilized so that any 14CO2 produced would represent mevalonate shunt pathway activity. The isolated perfused kidney was used to eliminate confounding variables. In eight control kidneys perfused for 2 hr 62 +/- 2% of the MVA was removed from the perfusate compared to 50 +/- 2% in five nephrotic kidneys (p less than .006). Urinary MVA recovery was 22 +/- 2% in controls. 15 +/- 1% in nephrotics (p less than .05). The incorporation of 14C into renal tissue lipids was not different in the two groups. Recovery of 14CO2 was two times greater in controls than in nephrotics (p less than .006). Inulin clearance per gram of kidney and sodium reabsorption were similar for the two groups. Isolated perfused kidneys from nephrotic rats metabolize MVA abnormally such that less is excreted, less is oxidized, and more is available for recirculation to the liver. This occurs independently of hypoalbuminemia, a change in glomerular filtration rate, or an overt histo-pathologic lesion. These events create an environment for increased hepatic cholesterol synthesis.

Animals↗
PubMed2004

Ageing and oxidative stress: a role for dolichol in the antioxidant machinery of cell membranes?

Dolichol is a polyprenol compound broadly distributed in membranes, biosynthetized by the general isoprenoid pathway from acetate via mevalonate and farnesyl pyrophosphate. Dolichol lays inside the membrane between the two leaflets of the lipid bilayer very close to the tail of phospholipid fatty acids. No definite catabolic pathways for this molecule have yet been identified. Evidence is produced that dolichol levels increase dramatically with increasing age; that anti-ageing caloric restriction retards this age-associated change; that dolichol may act as a radical scavenger of peroxidized lipids belonging to the cell membranes. In view of the polyunsaturated fatty acids (PUFA), dolichol and Vitamin E location and stechiometry, it is proposed that molecules might interact each-other to form a highly matched free-radical-transfer chain, whose malfunctioning might be involved in statin toxicity and neurodegenerative diseases.

Aging↗
PubMed1998

Phenylacetate inhibits isoprenoid biosynthesis and suppresses growth of human pancreatic carcinoma.

BACKGROUND: Phenylacetate is growth inhibitor for a variety of tumors at concentration that have been safely achieved in human beings. This antitumor effect is related to inhibition of the isoprenoid synthetic pathway by blocking the enzyme, mevalonate pyrophosphate (MVAPP) decarboxylase. The purpose of this study was to evaluate the effects of phenylacetate on human pancreatic carcinoma. METHODS: For in vitro studies, six human pancreatic carcinoma cell lines (BxPc, AsPc, MIAPaCa-2 Panc-1, CFPAc, and HS 766T) were studied. For in vivo studies, nude mice were inoculated with pancreatic cells (BxPc and MIA PaCa-2) and randomized to receive phenylacetate or saline control. RESULTS: Phenylacetate produces reversible in vitro growth arrest at doses of 2.5 to 10 mmol. The antiproliferative effect is cytostatic, producing accumulation of cells in G1, and is not associated with cell toxicity. Systemic treatment of nude mice bearing heterotopic human pancreatic carcinoma results in growth inhibition of tumors without host toxicity. Phenylacetate blocks the processing of mevalonate to isopentenyl-pyrophosphate by inhibiting MVAPP and exhibits suppression of biosynthetic pathways requiring isoprenoids, including cholesterol and dolichol biosynthesis, protein glycosylation, and isoprenylation of proteins. CONCLUSIONS: These results indicate that phenylacetate has cytostatic activity in pancreatic carcinoma and support the conclusion that suppression of multiple biosynthetic pathways requiring isoprenoids is contributing to the drug's antiproliferative action. The safety profile and efficacy of phenylacetate make it an attractive agent for the treatment of pancreatic cancer.

Animals↗
PubMed2006

Relationships among the biosyntheses of ubiquinone, carotene, sterols, and triacylglycerols in Zygomycetes.

The Zygomycetes Phycomyces blakesleeanus and Blakeslea trispora are actual or potential sources of beta-carotene, ergosterol, ubiquinone, edible oil, and other compounds. By feeding [14C]acetyl-CoA, L-[14C]leucine, or R-[14C]mevalonate in the presence of excess unlabeled glucose, we found that ubiquinone (the terpenoid moiety), beta-carotene, and triacylglycerols were made from separate pools of all their common intermediates; the pools for ubiquinone and ergosterol were indistinguishable. Fatty acids were not labeled from mevalonate, showing the absence in these fungi of a shunt pathway that would recycle carbon from mevalonate and its products back to central metabolism. The overproduction of carotene in a Phycomyces mutant and in sexually mated cultures of Blakeslea modified the relative use of labeled and unlabeled carbon sources in the production of carotene, but not of the other compounds. We concluded that carotene, ubiquinone, and triacylglycerols are synthesized in separate subcellular compartments, while sterols and ubiquinone are synthesized in the same compartments or in compartments that exchange precursors. Carotene biosynthesis was regulated specifically and not by flow diversion in a branched pathway.

Acetyl Coenzyme A↗
PubMed2002

The effects of lovastatin and simvastatin on the diurnal periodicity of plasma mevalonate concentrations in patients with heterozygous familial hypercholesterolemia.

Animal and human studies have shown that the biosynthesis of cholesterol exhibits diurnal periodicity with nocturnal increases in the level of cholesterol precursors. Dietary cholesterol, which increases the intracellular pool of cholesterol and plasma cholesterol levels, has been shown to blunt the nocturnal increases in cholesterol biosynthesis. Patients with heterozygous familial hypercholesterolemia (FH) have very high levels of plasma low-density lipoprotein cholesterol (LDL) due to their reduced ability to metabolize LDL particles. The present studies were carried out to determine whether diurnal variations in cholesterol synthesis occur in FH patients and to test the effects of 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) reductase inhibitors on the diurnal cycle of cholesterol biosynthesis in these patients. Diurnal rates of cholesterol synthesis were assessed by measuring the plasma concentrations of mevalonate, an intermediate in the pathway of cholesterol biosynthesis. Female FH patients exhibited a diurnal pattern in plasma mevalonate levels similar to that previously reported in controls with peak values occurring at night. Treatment with lovastatin and simvastatin (40 mg b.i.d.) significantly reduced 24-h mean plasma mevalonate levels from baseline values. Administration of lovastatin in the evening reduced the nocturnal increases in mevalonate levels, and the administration of simvastatin completely abolished the nighttime rise. These results demonstrate that inhibition of cholesterol biosynthesis by lovastatin and simvastatin modifies the normal diurnal rhythm of cholesterol biosynthesis in female FH patients.

Adult↗
PubMed1993

Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Tocotrienols are natural farnesylated analogues of tocopherols which decrease hepatic cholesterol production and reduce plasma cholesterol levels in animals. For several cultured cell types, incubation with gamma-tocotrienol inhibited the rate of [14C]acetate but not [3H] mevalonate incorporation into cholesterol in a concentration- and time-dependent manner, with 50% inhibition at approximately 2 microM and maximum approximately 80% inhibition observed within 6 h in HepG2 cells. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase total activity and protein levels assayed by Western blot were reduced concomitantly with the decrease in cholesterol synthesis. In HepG2 cells, gamma-tocotrienol suppressed reductase despite strong blockade by inhibitors at several steps in the pathway, suggesting that isoprenoid flux is not required for the regulatory effect. HMG-CoA reductase protein synthesis rate was moderately diminished (57% of control), while the degradation rate was increased 2.4-fold versus control (t1/2 declined from 3.73 to 1.59 h) as judged by [35S]methionine pulse-chase/immunoprecipitation analysis of HepG2 cells treated with 10 microM gamma-tocotrienol. Under these conditions, the decrease in reductase protein levels greatly exceeded the minor decrease in mRNA (23 versus 76% of control, respectively), and the low density lipoprotein receptor protein was augmented. In contrast, 25-hydroxycholesterol strongly cosuppressed HMG-CoA reductase protein and mRNA levels and the low density lipoprotein receptor protein. Thus, tocotrienols influence the mevalonate pathway in mammalian cells by post-transcriptional suppression of HMG-CoA reductase, and appear to specifically modulate the intracellular mechanism for controlled degradation of the reductase protein, an activity that mirrors the actions of the putative non-sterol isoprenoid regulators derived from mevalonate.

Acetates↗