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HMG-CoA Reductase (hmg-coa + reductase)
Terms modified by HMG-CoA Reductase Selected AbstractsSodium lauryl sulphate alters the mRNA expression of lipid-metabolizing enzymes and PPAR signalling in normal human skin in vivoEXPERIMENTAL DERMATOLOGY, Issue 12 2009Hans Törmä Abstract:, Detergents irritate skin and affect skin barrier homeostasis. In this study, healthy skin was exposed to 1% sodium lauryl sulphate (SLS) in water for 24 h. Biopsies were taken 6 h to 8 days post exposure. Lipid patterns were stained in situ and real-time polymerase chain reaction (PCR) was used to examine mRNA expression of enzymes synthesizing barrier lipids, peroxisome proliferator-activated receptors (PPAR) and lipoxygenases. The lipid pattern was disorganized from 6 h to 3 days after SLS exposure. Concomitant changes in mRNA expression included: (i) reduction, followed by induction, of ceramide-generating ,-glucocerebrosidase, (ii) increase on day 1 of two other enzymes for ceramide biosynthesis and (iii) persistent reduction of acetyl-CoA carboxylase-B, a key enzyme in fatty acid synthesis. Surprisingly, the rate-limiting enzyme in cholesterol synthesis, HMG-CoA reductase, was unaltered. Among putative regulators of barrier lipids synthesis, PPAR, and PPAR, exhibited reduced mRNA expression, while PPAR,/, and LXR, were unaltered. Epidermal lipoxygenase-3, which may generate PPAR, agonists, exhibited reduced expression. In conclusion, SLS induces reorganization of lipids in the stratum corneum, which play a role in detergents' destruction of the barrier. The changes in mRNA expression of enzymes involved in synthesizing barrier lipids are probably important for the restoration of the barrier. [source] Combined overexpression of genes of the ergosterol biosynthetic pathway leads to accumulation of sterols in Saccharomyces cerevisiaeFEMS YEAST RESEARCH, Issue 1 2003Markus Veen GC, gas chromatography; TLC, thin layer chromatography Abstract Genes of the post-squalene ergosterol biosynthetic pathway in Saccharomyces cerevisiae have been overexpressed in a systematic approach with the aim to construct yeast strains that produce high amounts of sterols from a squalene-accumulating strain. This strain had previously been deregulated by overexpressing a truncated HMG-CoA reductase (tHMG1) in the main bottleneck of the early ergosterol pathway. The overexpression of the gene ERG1 (squalene epoxidase) induced a significant decrease of the direct substrate squalene, a high increase of lanosterol, and a small increase of later sterols. The overexpression of the ERG11 gene encoding the sterol-14,-demethylase resulted in a decrease of lanosterol and an increase of downstream sterols. When these two genes were simultaneously overexpressed, later sterols from zymosterol to ergosterol accumulated and the content of squalene was decreased about three-fold, indicating that these steps had limited the transformation of squalene into sterols. The total sterol content in this strain was three-fold higher than in a wild-type strain. [source] Pleiotropic phenotypes caused by an opal nonsense mutation in an essential gene encoding HMG-CoA reductase in fission yeastGENES TO CELLS, Issue 6 2009Yue Fang Schizosaccharomyces pombe genome contains an essential gene hmg1+ encoding the sterol biosynthetic enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Here, we isolated an allele of the hmg1+ gene, hmg1-1/its12, as a mutant that showed sensitivities to high temperature and to FK506, a calcineurin inhibitor. The hmg1-1 allele contained an opal nonsense mutation in its N-terminal transmembrane domain, yet in spite of the mutation a full-length protein was produced, suggesting a read-through termination codon. Consistently, overexpression of the hmg1-1 mutant gene suppressed the mutant phenotypes. The hmg1-1 mutant showed hypersensitivity to pravastatin, an HMGR inhibitor, suggesting a defective HMGR activity. The mutant treated with FK506 caused dramatic morphological changes and showed defects in cell wall integrity, as well as displayed synthetic growth phenotypes with the mutant alleles of genes involved in cytokinesis and cell wall integrity. The mutant exhibited different phenotypes from those of the disruption mutants of ergosterol biosynthesis genes, and it showed normal filipin staining as well as showed normal subcellular localization of small GTPases. These data suggest that the pleiotropic phenotypes reflect the integrated effects of the reduced availability of ergosterol and various intermediates of the mevalonate pathway. [source] Abstracts: The effects of licorice leaf extract on ceramide and hyaluronan synthesisINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 5 2010Akinori Kiso pp.267,273 Both water-holding and permeability barrier function in the stratum corneum (SC) are essential for keeping skin moisture. Intercellular lipids in SC, which are composed mainly of cholesterol, fatty acids, and ceramides, play a crucial role for maintaining the function in SC. The object of our study is to find active ingredients from plant extracts for enhancing the abilities of skin hydration and barrier repair by focusing on the synthesis of ceramides. As a result, we found that licorice leaf extract is a promising ingredient showing not only an increase of mRNA expression levels of serine palmytoyltransferase (SPT) and sphingomyelinase related to ceramide biosynthesis in keratinocytes but also syntheses of ceramides in a 3D skin model and in human skin. Furthermore, licorice leaf extract showed an increase of mRNA expression levels of HMG-CoA reductase (HMGCR) related to cholesterol biosynthesis and an increase of hyaluronan (HA) production in in vitro tests. One of the principles isolated from licorice leaf extract, 6-prenyl-naringenin, was thought to be one of the active components. These results suggested that licorice leaf extract may be a useful ingredient for skin care due to the synthesis of intercellular lipids and HA [source] Lipid-lowering efficacy of 3,4-di(OH)-phenylpropionic L -leucine in high-cholesterol fed ratsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 1 2005Soon-Ja Kim Abstract A preliminary study revealed that 3,4-di(OH)-hydrocinnamate (HC), a polyphenolic compound, lowered the plasma lipids in high-cholesterol fed rats. Accordingly, this study was designed to test the lipid-lowering efficacy of a synthetic derivative, 3,4-di(OH)-phenylpropionic (L -leucine) amide (PPLA), in rats fed a high-cholesterol (1%, wt/wt) diet. As such, HC or PPLA was given as supplement to a high-cholesterol diet for 6 weeks at a dose of 0.137 mmol/100 g diet. The supplementation of HC and PPLA significantly lowered the plasma and hepatic cholesterol and triglyceride levels compared to the control group. The activities of hepatic HMG-CoA reductase (164 ± 9.12 and 124.74 ± 17.09 pmol/min/mg protein vs. 245.41 ± 13.01 pmol/min/mg protein, p < 0.05) and ACAT (411.49 ± 11.48 and 334.35 ± 17.68 pmol/min/mg protein vs. 490.41 ± 16.69 pmol/min/mg protein, p < 0.05) were significantly lower in the HC- and PPLA-supplemented groups than in the control group. However, PPLA was more effective in inhibiting the enzyme activities than HC. The excretion of neutral sterol was significantly higher in HC- and PPLA-supplemented groups than in the control group. Therefore, these results indicate that PPLA, a leucine-attached version of HC, exhibited a similar significant hypocholesterolemic effect to HC in rats fed a high-cholesterol diet. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:25,31, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20054 [source] Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductaseJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5 2010S. Kato Abstract Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies. [source] Amelioration of Cadmium-Induced Oxidative Stress, Impairment in Lipids and Plasma Lipoproteins by the Combined Treatment with Quercetin and ,-Tocopherol in RatsJOURNAL OF FOOD SCIENCE, Issue 7 2010S. Milton Prabu Abstract:, Cadmium (Cd) exposure results in numerous pathological consequences including oxidative stress and dyslipidemia. The present study was designed to investigate the efficacy of combined treatment with quercetin (QE) and ,-tocopherol (AT) against Cd-induced oxidative stress and alterations in lipids and lipoproteins in the plasma and liver of rats. Oral administration of Cd (5 mg/kg bw/d) for 4 wk has shown a significant (P < 0.05) increase in thiobarbituric acid reactive substances (TBARS), lipid hydro peroxides (LOOH), total cholesterol, low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), free fatty acids (FFA), phospholipids (PL), triglycerides (TGs), and the activity of hydroxyl-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) in plasma with a significant (P > 0.05) reduction in the levels of reduced glutathione (GSH), high density lipoprotein cholesterol (HDL-C), and the activity of lecithin cholesterol acyl transferase (LCAT) in plasma. In addition, the levels of hepatic thiobarbituric acid reactive substances (TBARS), LOOH, conjugated dienes (CD), protein carbonyls (PC), and the activity of HMG-CoA reductase, levels of cholesterol, FFA, and TGs were significantly (P > 0.05) increased and the level of PL is significantly (P > 0.05) decreased along with the decreased activity of LCAT in the liver of Cd-treated rats. Oral supplementation with QE (50 mg/kg bw/d) and AT (50 mg/kg bw/d) for 4 wk in Cd intoxicated rats significantly (P > 0.05) has reduced the plasma levels of TBARS, LOOH, GSH, cholesterol, FFA, TGs, VLDL-C, LDL-C, and the activity of HMG-CoA and significantly (P > 0.05) has increased the activity of LCAT and the plasma levels of HDL-C. The oral supplementation also significantly (P > 0.05) has reduced the hepatic oxidative stress markers, cholesterol, TGs, FFA, and significantly (P > 0.05) has increased the LCAT activity and the PL in liver. Our results indicate that the combined treatment with QE and AT has normalized all the previously mentioned biochemical parameters in Cd-intoxicated rats than the individual treatments. The combined treatment has provided remarkable protection against Cd-induced oxidative stress and alterations in lipid metabolism and, thereby, reduced the Cd-mediated cardiovascular diseases. [source] Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG-CoA reductaseJOURNAL OF MOLECULAR RECOGNITION, Issue 4 2008Valeriy V. Pak Abstract This study presents an approach that can be used to search for lead peptide candidates, including unconstrained structures in a recognized sequence. This approach was performed using the design of a competitive inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). In a previous design for constrained peptides, a head-to-tail cyclic structure of peptide was used as a model of linear analog in searches for lead peptides with a structure close to an active conformation. Analysis of the conformational space occupied by the peptides suggests that an analogical approach can be applied for finding a lead peptide with an unconstrained structure in a recognized sequence via modeling a cycle using fixed residues of the peptide backbone. Using the space obtained by an analysis of the bioactive conformations of statins, eight cyclic peptides were selected for a peptide library based on the YVAE sequence as a recognized motif. For each cycle, the four models were assessed according to the design criterion ("V" parameter) applied for constrained peptides. Three cyclic peptides (FGYVAE, FPYVAE, and FFYVAE) were selected as lead cycles from the library. The linear FGYVAE peptide (IC50,=,0.4,µM) showed a 1200-fold increase the inhibitory activity compared to the first isolated LPYP peptide (IC50,=,484,µM) from soybean. Experimental analysis of the modeled peptide structures confirms the appropriateness of the proposed approach for the modeling of active conformations of peptides. Copyright © 2008 John Wiley & Sons, Ltd. [source] Effects of statins on adhesion molecule expression in endothelial cellsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2003Y. Dimitrova Summary.,Background:,Inhibitors of HMG-CoA reductase are widely used to prevent atherosclerosis progression. The expression of adhesion molecules on activated endothelial cells (EC) is an important step in the initiation and progression of atherosclerosis. Objectives:,We investigated whether adhesion molecule expression on activated EC is influenced by simvastatin, fluvastatin and pravastatin and, if so, by which mechanisms. Methods:,Human EC from umbilical veins or saphenous veins were pretreated overnight with statins with or without mevalonate, and also for simvastatin or fluvastatin with the isoprenoid intermediates, farnesyl pyrophosphate (FPP), or geranylgeranyl pyrophosphate (GGPP). After 4,6 h activation with tumor necrosis factor (TNF)-, or lipopolysaccharide (LPS), surface adhesion molecule expression was evaluated by ELISA and by flow cytometry. The same experiments were performed with selective inhibitors of geranylgeranyltransferase (GGTI-286) and farnesyltransferase (FTI-277). Results:,Pretreatment with simvastatin, fluvastatin or pravastatin potentiated the TNF-, and LPS-induced expression of E-selectin and VCAM-1, and mevalonate reversed the potentiating effect of these statins. GGPP also reversed the potentiating effect of simvastatin or fluvastatin on adhesion molecule expression, while FPP only partially reversed this effect. Furthermore, GGTI-286, but not FTI-277, mimicked the effect of simvastatin by increasing the TNF-,-mediated overexpression of E-selectin. Conclusions:,Statins increase E-selectin- and VCAM-1-induced expression on vascular endothelial cells stimulated with TNF-, or LPS. The inhibition of geranylgeranylated proteins could contribute to this effect. [source] Statins and progressive renal diseaseMEDICINAL RESEARCH REVIEWS, Issue 1 2002Michele Buemi Abstract Thanks to the administration of hypocholesterolemic drugs, important advances have been made in the treatment of patients with progressive renal disease. In vitro and in vivo findings demonstrate that statins, the inhibitors of HMG-CoA reductase, can provide protection against kidney diseases characterized by inflammation and/or enhanced proliferation of epithelial cells occurring in rapidly progressive glomerulonephritis, or by increased proliferation of mesangial cells occurring in IgA nephropathy. Many of the beneficial effects obtained occur independent of reduced cholesterol levels because statins can directly inhibit the proliferation of different cell types (e.g., mesangial, renal tubular, and vascular smooth muscle cells), and can also modulate the inflammatory response, thus inhibiting macrophage recruitment and activation, as well as fibrosis. The mechanisms underlying the action of statins are not yet well understood, although recent data in the literature indicate that they can directly affect the proliferation/apoptosis balance, the down-regulation of inflammatory chemokines, and the cytogenic messages mediated by the GTPases Ras superfamily. Therefore, as well as reducing serum lipids, statins and other lipid-lowering agents may directly influence intracellular signaling pathways involved in the prenylation of low molecular weight proteins that play a crucial role in cell signal transduction and cell activation. Statins appear to have important potential in the treatment of progressive renal disease, although further studies are required to confirm this in humans. © 2001 John Wiley & Sons, Inc. Med Res Rev, 22, No. 1, 76,84, 2002 [source] Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placentaMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 6 2008Charles Marseille-Tremblay Abstract Maternal hypercholesterolemia (HC) during pregnancy and gestational diabetes mellitus (GDM) are associated with disturbance of fetal development which may also modify key features of placental functions. In this study, we evaluated the impact of maternal hypercholesterolemia on placental cholesterol and lipid metabolism in 59 women classified in two groups according to the median concentration of plasma total cholesterol (6.42 mM). The impact of GDM was also evaluated on the metabolism of placentas obtained from 7 insulin-treated GDM and 7 non-GDM women. We showed that high maternal circulating cholesterol is associated with a significant increase in the LDL-cholesterol, ApoB-100 and triglyceride concentrations in the maternal blood. However the level of cholesterol in the venous cord blood and placenta remains unchanged in response to modification in maternal cholesterol profile. The levels of Fatty acid synthase (FAS) and SREBP-2 expressions in placenta are significantly increased in the HC group while expression of both sterol regulatory element-binding proteins-1 (SREBP-1) and HMG-CoA reductase (HMGR) are not modified. GDM is not associated with modification in the maternal lipid profile but it increases the concentration of inflammatory cytokines (IL-1, and TNF-,) in placenta which correlates with a dramatic induction of FAS expression without affecting the expression of mature SREBPs proteins. In conclusion, our study suggests that in placenta, expressions of key proteins involved in de novo lipid synthesis are affected by changes in maternal metabolism (HC and GDM) that may subsequently affect fetal development. Mol. Reprod. Dev. 75: 1054,1062, 2007. © 2007 Wiley-Liss, Inc. [source] Ergosterol peroxide from an edible mushroom suppresses inflammatory responses in RAW264.7 macrophages and growth of HT29 colon adenocarcinoma cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2007M Kobori Background and purpose: 5,,8,-Epidioxy-22E -ergosta-6, 22-dien-3,-ol (ergosterol peroxide) is a major antitumour sterol produced by edible or medicinal mushrooms. However, its molecular mechanism of action has yet to be determined. Here, we examine the anticancer and anti-inflammatory effects of ergosterol peroxide. Experimental approach: After treating RAW264.7 macrophages with LPS and purified ergosterol peroxide or ergosterol, we determined LPS-induced inflammatory cytokines, nuclear DNA binding activity of transcription factors and phosphorylation of MAP kinases (MAPKs). HT29 colorectal adenocarcinoma cells were treated with ergosterol peroxide for 5 days. To investigate the antitumour properties of ergosterol peroxide, we performed DNA microarray and RT-PCR analyses and determined the reactive oxygen species (ROS) in HT29 cells. Key results: Ergosterol peroxide suppressed LPS-induced TNF-, secretion and IL-1,/, expression in RAW264.7 cells. Ergosterol peroxide and ergosterol suppressed LPS-induced DNA binding activity of NF-,B and C/EBP,, and inhibited the phosphorylation of p38, JNK and ERK MAPKs. Ergosterol peroxide down-regulated the expression of low-density lipoprotein receptor (LDLR) regulated by C/EBP, and HMG-CoA reductase (HMGCR) in RAW264.7 cells. In addition, ergosterol peroxide showed cytostatic effects on HT29 cells and increased intracellular ROS. Furthermore, ergosterol peroxide induced the expression of oxidative stress-inducible genes, and the cyclin-dependent kinase inhibitor CDKN1A, and suppressed STAT1 and interferon-inducible genes. Conclusion and Implication: Our results suggest that ergosterol peroxide and ergosterol suppress LPS-induced inflammatory responses through inhibition of NF-,B and C/EBP, transcriptional activity, and phosphorylation of MAPKs. Moreover, ergosterol peroxide appears to suppress cell growth and STAT1 mediated inflammatory responses by altering the redox state in HT29 cells. British Journal of Pharmacology (2007) 150, 209,219. doi:10.1038/sj.bjp.0706972 [source] Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the ratBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2000Maria Álvarez De Sotomayor Vascular effects of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, were studied in conductance (aorta) and resistance vessels (branch II or III of superior mesenteric artery, SMA) of the rat (12,14 weeks old). Simvastatin produced relaxation of both aorta and SMA, with and without functional endothelium. These responses were inhibited by the product of HMG-CoA reductase, mevalonate (1 mmol l,1). In vessels with functional endothelium, the NO-synthase inhibitor, L -NG -nitroarginine (L -NOARG, 30 ,mol l,1), inhibited simvastatin-induced relaxation. In the presence of L -NOARG, relaxation to simvastatin was lower in vessels with endothelium than in endothelium-denuded arteries without L -NOARG. The cyclo-oxygenase inhibitor, indomethacin (10 ,mol l,1), abolished endothelium-dependent component of the response to simvastatin in both arteries. The combination of L -NOARG plus indomethacin did not produce further inhibition. The Tp receptor antagonist, GR 32191B (3 ,mol l,1), did not affect relaxation in aorta but it reduced response to low concentrations of simvastatin in SMA. However, the inhibitory effect of L -NOARG was less marked in the presence of GR 32191B in aorta but not in SMA. The endothelium-dependent relaxation to simvastatin was inhibited by the superoxide dismutase (SOD, 100 u ml,1) or by the tyrosine kinase inhibitor, genistein (30 ,mol l,1) in the two arteries. The present study shows that simvastatin produces relaxation of conductance and small arteries through mevalonate-sensitive pathway. The endothelium-dependent relaxation to simvastatin involves both NO and vasodilator eicosanoids by a mechanism sensitive to SOD, and to genistein. Also, the results highlighted participation in the aorta of endothelial vasoconstrictor eicosanoids acting on the Tp receptor after blockage of NO synthase only. British Journal of Pharmacology (2000) 131, 1179,1187; doi:10.1038/sj.bjp.0703668 [source] STUDIES ON THE EXPRESSION LEVELS OF STEROL-METABOLIZING ENZYMES IN THE OBESE MODEL SHR/NDmcr- cp RATSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 2004Makiko Kudo SUMMARY 1.,Expression levels of four key enzymes of cholesterol metabolism, namely 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lanosterol 14-demethylase (CYP51), cholesterol 7,-hydroxylase (CYP7A1) and sterol 12,-hydroxylase (CYP8B1), in metabolic syndrome model rats (SHR/NDmcr-cp) were examined. 2.,Decreased expression of CYP51, which may be linked to the development of obesity, was found in the rats. 3.,Expression of CYP8B1 was significantly higher in young rats. 4.,No substantial change was observed in the mRNA levels of the dominant rate-limiting enzymes of sterol metabolism, namely HMG-CoA reductase and CYP7A1, in the rats. 5.,These findings suggest that the expression levels of two key enzymes managing the downstream parts of the cholesterol-metabolizing pathways are altered in the rats, although little change was observed in the expression levels of the dominant rate-limiting enzymes of cholesterol metabolism. 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