Mevalonic Acid Research Articles

The ins and outs of cholesterol in the vertebrate retina

The vertebrate retina has multiple demands for utilization of cholesterol and must meet those demands either by synthesizing its own supply of cholesterol or by importing cholesterol from extraretinal sources, or both. Unlike the blood-brain barrier, the blood-retina barrier allows uptake of cholesterol from the circulation via a lipoprotein-based/receptor-mediated mechanism. Under normal conditions, cholesterol homeostasis is tightly regulated; also, cholesterol exists in the neural retina overwhelmingly in unesterified form, and sterol intermediates are present in minimal to negligible quantities. However, under certain pathological conditions, either due to an inborn error in cholesterol biosynthesis or as a consequence of exposure to selective inhibitors of enzymes in the cholesterol pathway, the ratio of sterol intermediates to cholesterol in the retina can rise dramatically and persist, in some cases resulting in progressive degeneration that significantly compromises the structure and function of the retina. Although the relative contributions of de novo synthesis versus extraretinal uptake are not yet known, herein we review what is known about these processes and the dynamics of cholesterol in the vertebrate retina and indicate some future avenues of research in this area.

Distribution and Biosynthesis of 20-Hydroxyecdysone in Plants ofAchyranthes japonicaNakai

There is increasing interest in phytoecdysteroids (PEs) because of their potential role in plant defense against insects. To understand the mechanism regulating their levels in plants, the fluctuation, distribution, and biosynthesis of PE 20-hydroxyecdysone (20E) examined in Achyranthes japonica. The total amount of 20E per individual plant initially remained at a constant level, and increased markedly after the first leaf pair (LP) stage, while the concentration of 20E in a given plant decreased rapidly during vegetative growth. In addition, the incorporation of [2-(14)C]-mevalonic acid into 20E did not differ significantly depending on plant organs and developmental stages, suggesting that biosynthesis of 20E is not restricted to particular organs or growth stages.

540 Adverse Reactions in Statin Therapy at Younger and Children Older Then Twelve Years

Background: Obesity in childhood bodes ill for future cardiovascular risk. HMG-CoA reductase is an enzyme in the cholesterol biosynthetic pathway that catalyses the conversion of HMG-CoA to mevalonic acid. Statins are a class of drugs that lower the level of cholesterol in the blood by reducing the production of cholesterol by the liver. Aims: The most controversial change appears to have been the inclusion of statins as potential firstline pharmacologic agents in older children. Methods: High-risk children, include those who are obese or overweight and who also have high blood pressure, or diabetes, or a positive family history of either high cholesterol or early heart disease. The safety of statins in children and adolescents is based on trials that have ranged in duration from six months to one year. Results: Inhibition of this enzyme in the liver results in decreased cholesterol synthesis as well as increased synthesis of LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream. The first results can be seen after one week of use and the effect is maximal after four to six weeks. No serious laboratory adverse events were reported during follow-up, and statin treatment had no untoward effects on sexual maturation. Conclusion: The recommendation to use statins in childhood seems to have hit a collective nerve, perhaps awakening us to the fuller implications of the obesity epidemic. Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis.

Molecular cloning and expression analysis of a new putative gene encoding 3-hydroxy-3-methylglutaryl-CoA synthase from Salvia miltiorrhiza

A new putative gene encoding 3-hydroxy-3-methylglutaryl coenzyme A synthase (designated as SmHMGS, GenBank Accession No. FJ785326), which catalyses the condensation of acetyl-CoA and acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA as an early step in the mevalonic acid pathway, was isolated from young leaves of Salvia miltiorrhiza by rapid amplification of cDNA ends (RACE) for the first time. The full-length cDNA of the putative SmHMGS was 1,655 bp containing a 1,381 bp open reading frame (ORF) encoding a polypeptide of 460 amino acids. Comparative and bioinformatic analyses revealed that SmHMGS showed extensive homology with HMGSs from other plant species. Phylogenetic tree analysis indicated that SmHMGS belonged to the plant HMGS super family and had the closest relationship with HMGS from Hevea brasiliensis. Tissue expression pattern analysis revealed that the putative SmHMGS was constitutively expressed in all the tested tissues and strong in leaf, moderate in stem, weak in root, which was in contrast to SmHMGR reported before. The putative SmHMGS was found to be an elicitor-responsive gene, which could be induced by exogenous elicitors, including salicylic acid (SA) and methyl jasmonate (MJ). These results will help in understanding the role of HMGS in tanshinones biosynthesis in S. miltiorrhiza.

Linalool Dehydratase-Isomerase, a Bifunctional Enzyme in the Anaerobic Degradation of Monoterpenes

Castellaniella (ex Alcaligenes) defragrans strain 65Phen mineralizes monoterpenes in the absence of oxygen. Soluble cell extracts anaerobically catalyzed the isomerization of geraniol to linalool and the dehydration of linalool to myrcene. The linalool dehydratase was present in cells grown on monoterpenes, but not if grown on acetate. We purified the novel enzyme ∼1800-fold to complete homogeneity. The native enzyme had a molecular mass of 160 kDa. Denaturing gel electrophoresis revealed one single protein band with a molecular mass of 40 kDa, which indicated a homotetramer as native conformation. The aerobically purified enzyme was anaerobically activated in the presence of 2 mm DTT. The linalool dehydratase catalyzed in vitro two reactions in both directions depending on the thermodynamic driving forces: a water secession from the tertiary alcohol linalool to the corresponding acyclic monoterpene myrcene and an isomerization of the primary allylalcohol geraniol in its stereoisomer linalool. The specific activities (V(max)) were 140 nanokatals mg(-1) for the linalool dehydratase and 410 nanokatals mg(-1) for the geraniol isomerase, with apparent K(m) values of 750 μm and 500 μm, respectively. The corresponding open reading frame was identified and revealed a precursor protein with a signal peptide for a periplasmatic location. The amino acid sequence did not affiliate with any described enzymes. We suggest naming the enzyme linalool dehydratase-isomerase according to its bifunctionality and placing it as a member of a new protein family within the hydrolyases (EC 4.2.1.X).

Relevance of the mevalonate biosynthetic pathway in the regulation of bone marrow mesenchymal stromal cell-mediated effects on T-cell proliferation and B-cell survival

Bone marrow mesenchymal stromal cells can suppress T-lymphocyte proliferation but promote survival of normal and malignant B cells, thus representing a possible target for new therapeutic schemes. Here we defined the effects of cholesterol synthesis inhibitors on the interaction between these mesenchymal stromal cells and T or B lymphocytes. We exposed mesenchymal stromal cells to inhibitors, such as fluvastatin, of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, responsible for the synthesis of mevalonate, the precursor of cholesterol. Also, these cells were treated with manumycin A, a farnesyl transferase inhibitor which blocks the mevalonate-dependent isoprenylation of small guanosin triphosphate binding proteins. First, mesenchymal stromal cell morphology, cytoskeleton assembly, cell cycle, survival and cytokine production were evaluated. Then, these cells were co-cultured with either T or B lymphocytes and we analyzed: 1) the inhibition of T-cell proliferation to mitogenic stimuli; 2) B-cell survival. Fluvastatin altered the assembly of actin microfilaments, inactivated RhoA guanosin triphosphate binding protein, inhibited the S-phase of the cell cycle, induced apoptosis in a small fraction of cells but preserved cytokine production. Preincubation of mesenchymal stromal cells with fluvastatin, or manumycin A, down-regulated the expression of adhesion molecules, reduced cell-to-cell interactions and prevented the inhibition exerted by these stromal cells on CD3/T-cell receptor-induced lymphocyte proliferation. Mevalonic acid could revert morphological, phenotypic and functional effects of fluvastatin. Finally, fluvastatin significantly reduced the mesenchymal stromal cells-mediated rescue of B cells in the presence of dexamethasone, although it did not function in the absence of corticosteroids. Fluvastatin-mediated effects on bone marrow mesenchymal stromal cells were conceivably due to the inhibition of isoprenylation of small guanosin triphosphate binding proteins, occurring for the lack of mevalonate. Altogether these findings suggest that drugs acting on the mevalonate biosynthetic pathway can regulate mesenchymal stromal cell-induced T-cell suppression and B-lymphocyte survival.

Chemical indexes calculated for 8,11,13-trienabietane diterpenoids isolated from Swartzia species

The disparity found in the molecular structures of compounds isolated from nine plants of the Swartzia genus indicates that the Swartzia species that furnished cassane diterpenoids and triterpenoidal saponins are more recent, since these metabolites have adopted the mevalonic acid route of formation, abandoning the shikimic acid/acetate route that produces the isoflavonoids found in the remaining species. Chemical indexes calculated from the molecular structure diversities of sixteen 8,11,13-trien-abietane diterpenoids isolated from Swartzia langsdorffii and S. arborescens indicate that S. arborescens is more recent than S. langsdorffii. The results suggest a more evolved position in Swartzia species of the section Possira.

Structural and functional characterization of HMG-COA reductase from Artemisia annua.

Plants synthesize a great variety of isoprenoid products that are required not only for normal growth and development but also for their adaptive responses to environmental challenges. However, despite the remarkable diversity in the structure and function of plant isoprenoids, they all originate from a single metabolic precursor, mevalonic acid. The synthesis of mevalonic acid is catalysed by the enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG- CoA reductase). The analysis of the amino acid sequence of HMG-CoA reductase from Artemisia annua L. plant showed that it belongs to class I HMG-CoA reductase family. The three dimensional structure of HMG-CoA reductase of Artemisia annua has been generated from amino acid sequence using homology modelling with backbone structure of human HMG-CoA reductase as template. The model was generated using the SWISS MODEL SERVER. The generated 3-D structure of HMG-CoA reductase was evaluated at various web interfaced servers to checks the stereo interfaced quality of the structure in terms of bonds, bond angles, dihedral angles and non-bonded atom-atom distances, structural as well as functional domains etc. The generated model was visualized using the RASMOL. Structural analysis of HMG-CoA reductase from Artemisia annua L. plant hypothesize that the N and C-terminals are positioned in cytosol by the two membrane spanning helices and the C-terminals domain shows similarity to the human HMG-CoA reductase enzyme indicating that they both had potential catalytic similarities.

Statins inhibited erythropoietin-induced proliferation of rat vascular smooth muscle cells

Erythropoietin (EPO) directly stimulates the proliferation of vascular smooth muscle cells, and this is believed to be one of the mechanisms of vascular access failure of hemodialysis patients. However, precise mechanisms of the EPO-induced proliferation of vascular smooth muscle cells are not certain. HMG-CoA reductase inhibitors (statins) are primarily used to reduce cholesterol levels, but also exert other effects, including reno-protective effects. We evaluated the effect of several statins with various hydrophilicities on the EPO-induced proliferation of primary cultured rat vascular smooth muscle cells (VSMCs) in vitro. EPO significantly and concentration-dependently increased DNA synthesis as assessed by [ 3H]thymidine incorporation, cell proliferation as assessed by WST-1 assay, and activation of the p44/42MAPK pathway. Therapeutic doses of statins (pravastatin, simvastatin, atorvastatin and fluvastatin) in patients with hypercholesterolemia almost completely suppressed all of the EPO-induced effects in a concentration-dependent manner. Co-addition of mevalonic acid almost completely reversed the effects of statins. Statin alone did not affect the basal proliferation capacity of the cells. The effects were almost similar among the statins. We concluded that statins inhibited EPO-induced proliferation in rat VSMCs at least partly through their inhibition of HMG-CoA reductase activity. In the future, statins might prove useful for the treatment of EPO-induced hyperplasia of vascular access. Because the statins all showed comparable effects irrespective of their hydrophilicities, these effects might be a class effect.

Chemical indexes calculated for 8,11,13-trien-abietane diterpenoids isolated from Swartzia species

The disparity found in the molecular structures of compounds isolated from nine plants of the Swartzia genus indicates that the Swartzia species that furnished cassane diterpenoids and triterpenoidal saponins are more recent, since these metabolites have adopted the mevalonic acid route of formation, abandoning the shikimic acid/acetate route that produces the isoflavonoids found in the remaining species. Chemical indexes calculated from the molecular structure diversities of sixteen 8,11,13-trien-abietane diterpenoids isolated from Swartzia langsdorffii and S. arborescens indicate that S. arborescens is more recent than S. langsdorffii. The results suggest a more evolved position in Swartzia species of the section Possira.

The pigment-scent connection: Do mutations in regulatory vs. structural anthocyanin genes differentially alter floral scent production in Ipomoea purpurea?

Many recent studies attempting to assess the biochemical connections between anthocyanin biosynthesis and floral scent production have yielded limited insights due in part to a focus on either field phenotypes of unknown genetic background or artificial genetic manipulation. In this study, we seek to more precisely explore the mechanistic connections between floral scent and color in Ipomoea purpurea by comparing inbred lines of wild-type purple flowered plants to lines of two naturally occurring color mutants: albino individuals created by a chalcone synthase ( A locus) loss-of-function mutation and rayed individuals that result from a non-functional transcription factor ( W locus). We found that I. purpurea floral scent is dominated by the two sesquiterpene hydrocarbons, ( E)-β-caryophyllene and germacrene D, with small amounts of several other sesquiterpenoid compounds. These 15 carbon volatiles are derived from the mevalonic acid biosynthetic pathway, which has no structural precursor relationship with anthocyanin pigments. Thus, there is no direct pleiotropic relationship and, accordingly, we found no differences in overall scent production between purple-flowered and albino individuals. In contrast, rayed plants showed greater emission of several compounds when compared to their wild-type counterparts, suggesting that the specific mutant regulatory region in this phenotype could have an indirect effect on volatile production either through changes to overall metabolic flux or alteration of sesquiterpene synthase gene expression or enzyme activity. Future research should explore these possible roles for transcription factors across multiple biochemical pathways. There were no differences in floral scent composition or emission rate between the offspring of parents from the same line, suggesting that scent phenotype was conserved within each inbred line. However, there were differences in floral scent between inbred lines, suggesting that a number of genetic elements must contribute to overall scent production in this species.

Lipophilic statins prevent matrix metalloproteinase-mediated cartilage collagen breakdown by inhibiting protein geranylgeranylation

ObjectiveTo investigate if statins prevent cartilage degradation and the production of collagenases and gelatinases in bovine nasal and human articular cartilage after proinflammatory cytokine stimulation.MethodsIn a cartilage degradation model, the...

Overexpression of PgSQS1 Increases Ginsenoside Production and Negatively Affects Ginseng Growth Rate in Panax ginseng

The medicinal plant Panax ginseng (P. ginseng) contains various phytosterols and bioactive triterpene saponins (ginsenosides). Squalene synthase catalyzes the first committed step in ginsenoside biosynthesis. Transgenic plants of P. ginseng were generated by introducing the squalene synthase gene derived from P. ginseng. Adventitious roots of the transgenic ginseng grew best in B5 medium, and 2 g of inoculum secured an optimal growth rate. Two phytohormones, indolebutyric acid and 1-naphtalene acetic acid, increased root growth and decreased ginsenoside production. Treatment with two selected elicitors, chitosan and jasmonic acid, and a precursor of the isoprenoid pathway, mevalonic acid, enhanced ginsenoside production and retarded ginseng growth rate.

Biosynthesis of andrographolide in Andrographis paniculata

Andrographolide, a diterpene lactone, is isolated from Andrographis paniculata which is well known for its medicinal properties. The biosynthetic route to andrographolide was studied using [1- 13C]acetate, [2- 13C]acetate and [1,6- 13C 2]glucose. The peak enrichment of eight carbon atoms in the 13C NMR spectra of andrographolide suggested that deoxyxylulose pathway (DXP) is the major biosynthetic pathway to this diterpene. The contribution of the mevalonic acid pathway (MVA) is indicated by the observed 13C-labeling pattern, and because the labeling patterns indicate a simultaneous contribution of both methyl erythritol phosphate (MEP) and MVA pathways it can be deduced that cross-talk occurs between plastids and cytoplasm.

Plant volatiles

Plant volatiles are the metabolites that plants release into the air. The quantities released are not trivial. Almost one-fifth of the atmospheric CO2 fixed by land plants is released back into the air each day as volatiles. Plants are champion synthetic chemists; they take advantage of their anabolic prowess to produce volatiles, which they use to protect themselves against biotic and abiotic stresses and to provide information - and potentially disinformation - to mutualists and competitors alike. As transferors of information, volatiles have provided plants with solutions to the challenges associated with being rooted in the ground and immobile.

Biochemical Conservation and Evolution of Germacrene A Oxidase in Asteraceae

Sesquiterpene lactones are characteristic natural products in Asteraceae, which constitutes approximately 8% of all plant species. Despite their physiological and pharmaceutical importance, the biochemistry and evolution of sesquiterpene lactones remain unexplored. Here we show that germacrene A oxidase (GAO), evolutionarily conserved in all major subfamilies of Asteraceae, catalyzes three consecutive oxidations of germacrene A to yield germacrene A acid. Furthermore, it is also capable of oxidizing non-natural substrate amorphadiene. Co-expression of lettuce GAO with germacrene synthase in engineered yeast synthesized aberrant products, costic acids and ilicic acid, in an acidic condition. However, cultivation in a neutral condition allowed the de novo synthesis of a single novel compound that was identified as germacrene A acid by gas and liquid chromatography and NMR analyses. To trace the evolutionary lineage of GAO in Asteraceae, homologous genes were further isolated from the representative species of three major subfamilies of Asteraceae (sunflower, chicory, and costus from Asteroideae, Cichorioideae, and Carduoideae, respectively) and also from the phylogenetically basal species, Barnadesia spinosa, from Barnadesioideae. The recombinant GAOs from these genes clearly showed germacrene A oxidase activities, suggesting that GAO activity is widely conserved in Asteraceae including the basal lineage. All GAOs could catalyze the three-step oxidation of non-natural substrate amorphadiene to artemisinic acid, whereas amorphadiene oxidase diverged from GAO displayed negligible activity for germacrene A oxidation. The observed amorphadiene oxidase activity in GAOs suggests that the catalytic plasticity is embedded in ancestral GAO enzymes that may contribute to the chemical and catalytic diversity in nature.

Abstract 5592: Lovastatin and low dose celecoxib decrease proliferation and inflammation in a cellular model of lung pre-malignancy

Abstract Statin drugs, such as lovastatin and pravastatin, block the cellular synthesis of cholesterol by inhibiting the function of HMG-CoA reductase. In a prospective study, patients undergoing statin treatment for prevention of atherosclerosis were at a lower risk of developing certain cancers, including lung and breast, suggesting a possible use for lovastatin in the chemoprevention of lung cancer. Here, we show that lovastatin dose-dependently decreases proliferation in both histologically normal and Kras-mutated human bronchial epithelial cells (HBECs) through the inhibition of cholesterol production. However, increased expression of PGE2, which we and others have shown to contribute to lung cancer progression, was noted with lovastatin treatment alone. Lovastatin up-regulates the production of PGE2 by up-regulating COX-2 expression and simultaneously down-regulating metabolism of PGE2 via down-regulation of 15-PGDH expression. Treatment with the cholesterol precursor, mevalonic acid, inhibited up-regulation of PGE2 and blocked dose-dependent anti-proliferative activity of lovastatin, indicating sterol-dependence. Treatment with both lovastatin and low dose (0.1uM) celecoxib, a COX-2 inhibitor, decreased PGE2 protein production in vector control and Kras-mutated HBECs. These findings suggest that the combination of lovastatin and low dose celecoxib overcomes up-regulation of PGE2 by lovastatin alone and that the combination represents a potentially effective lung cancer chemopreventative regimen worthy of further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5592.

A Novel Missense Mutation in MVK Associated With MK Deficiency and Dyserythropoietic Anemia

Mevalonate kinase deficiency (MKD) is a rare inborn error of metabolism caused by mutations in the mevalonate kinase (MVK) gene. The clinical phenotype is variable, ranging from the hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) to mevalonic aciduria (MA), a severe metabolic disease. We report here for the first time (to our knowledge) the case of a patient with MKD and congenital dyserythropoietic anemia. Clinical and laboratory characteristics of inflammatory attacks were compatible with HIDS, but mild dysmorphic features and elevated urinary mevalonic acid levels in the absence of an inflammatory attack suggested an intermediate phenotype between HIDS and MA. Genomic sequencing of the MVK gene revealed compound heterozygosity for a missense mutation previously described in MA (V310M) and a novel missense mutation (Y116H). By contrast, sequencing of the novel CDAII (SEC23B) gene revealed no mutations, suggesting that the bone marrow abnormalities were causally related to the MKD. Treatment with corticosteroids and colchicine directed at controlling the autoinflammatory disease resulted in improvement of the anemia.

684 NOVEL CANDIDATE GENE FOR PROSTATE CANCER (PC) SUSCEPTIBILITY, FARNECYL-DIPHOSPHATE FARNECYLTRANSFERASE 1 (FDFT1) : ASSOCIATIONS OF FDFT1 GENE VARIANTS WITH PC RISK, AND FDFT1 PROTEIN FUNCTION EVALUATION IN PC CELLS

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2010684 NOVEL CANDIDATE GENE FOR PROSTATE CANCER (PC) SUSCEPTIBILITY, FARNECYL-DIPHOSPHATE FARNECYLTRANSFERASE 1 (FDFT1): ASSOCIATIONS OF FDFT1 GENE VARIANTS WITH PC RISK, AND FDFT1 PROTEIN FUNCTION EVALUATION IN PC CELLS Hiroshi Matsui, Yuji Fukuma, Tatsuya Hamano, Hidekazu Koike, Yoshitaka Sekine, Nobuaki Ohtake, Seiji Nakata, and Kazuhiro Suzuki Hiroshi MatsuiHiroshi Matsui Maebashi, Japan More articles by this author , Yuji FukumaYuji Fukuma Maebashi, Japan More articles by this author , Tatsuya HamanoTatsuya Hamano Maebashi, Japan More articles by this author , Hidekazu KoikeHidekazu Koike Maebashi, Japan More articles by this author , Yoshitaka SekineYoshitaka Sekine Maebashi, Japan More articles by this author , Nobuaki OhtakeNobuaki Ohtake Takasaki, Japan More articles by this author , Seiji NakataSeiji Nakata Ashikaga, Japan More articles by this author , and Kazuhiro SuzukiKazuhiro Suzuki Maebashi, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1083AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We previously conducted genome-wide linkage analyses in 44 nuclear Japanese families affected with PC and concluded PC susceptibilities in Japan to be closely linked to D8S550 on 8p23 and D1S2667 on 1p36. The FDFT1 gene exists just under the peak marker, D8S550, on 8p23. This gene encodes squalene synthase (SQS), an important enzyme in the sterol branch of the mevalonic acid pathway. Relationships between lipid metabolism and PC, as well as epidemiological factors, appear to be underlying mechanisms. Herein, we evaluated the associations between FDFT1 variants and PC risk in the Japanese population and the function of SQS in PC cells. METHODS 1. Association study of FDFT1 polymorphisms: Probands from 115 families with familial PC (FPC), 138 with sporadic PC and 119 with benign prostatic hyperplasia as controls were studied. All study subjects belonged to the Japanese ethnic group. Genomic DNA was isolated from whole blood cells and genotyping of 5 SNPs (rs2645429, rs11549147, hCV25649966, rs1804473, rs2294136) was done using the TaqMan SNP Genotyping Assay. The associations of these SNP genotypes with FPC were evaluated using the chi-square test. 2. SQS functional analyses in PC cells: We found an association between being an A allele carrier of SNP rs2645429 and FPC. SNP rs2645429 is located in the FDFT1 promoter region. Vectors mutating this site to GG and to AA, prepared using mutagenesis, were transfected into COS-1 and LNCaP cells, respectively. We evaluated FDFT1 gene expression using Promoter-Reporter Assays and investigated changes in LNCaP and PC-3 cell proliferation with knock-down of FDFT1 using siRNA. RESULTS The odds ratio for the A allele carrier of SNP rs2645429 at the FDFT1 promoter region (1.86 [95% CI: 1.10-3.13, P=0.026]) was significantly higher in FPC than controls. The promoter-reporter assay revealed FDFT1 promoter activity to be decreased with the GG genotype at rs2645429 versus the AA genotype. The proliferation of PC cells was suppressed by FDFT1 knock-down using siRNA. CONCLUSIONS The significant differences in the A allele carrier at SNP rs2645429 between FPC and unaffected controls observed in this study are therefore considered to support the premise that the FDFT1 gene plays a significant role in PC susceptibility. SQS also appears to be involved in PC cell proliferation. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e267 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hiroshi Matsui Maebashi, Japan More articles by this author Yuji Fukuma Maebashi, Japan More articles by this author Tatsuya Hamano Maebashi, Japan More articles by this author Hidekazu Koike Maebashi, Japan More articles by this author Yoshitaka Sekine Maebashi, Japan More articles by this author Nobuaki Ohtake Takasaki, Japan More articles by this author Seiji Nakata Ashikaga, Japan More articles by this author Kazuhiro Suzuki Maebashi, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.