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Cholesterol Biosynthesis (cholesterol + biosynthesis)
Terms modified by Cholesterol Biosynthesis Selected AbstractsDifferent effects of pioglitazone and rosiglitazone on lipid metabolism in mouse cultured liver explantsDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2010Louiza Djaouti Abstract Background Pioglitazone (PIO) and rosiglitazone (ROSI) are widely used as oral antidiabetic agents for treatment of type 2 diabetes. Although these medications exert similar effects on blood glucose, recent clinical studies indicated that PIO has a more pronounced beneficial effect on lipid parameters than ROSI. In order to get further insight into the lipid effects of both drugs, we tested whether PIO, compared to ROSI, could exert direct effects on lipid liver metabolism in relation with plasma lipids. Methods We performed in vitro studies using mice liver slices incubated 21 h either with ROSI (1 µmol/L) or PIO (7.5 µmol/L). Results We showed that both glitazones slightly reduced HMG-CoA reductase mRNA levels at the same degree but only PIO reduced intracellular cholesterol content, suggesting an alteration of cholesterol uptake rather than an inhibition of cholesterol biosynthesis. This concept was supported by the reduction of scavenger receptor class B type I expression, hepatic lipase activity and high-density lipoprotein cholesterol uptake in PIO-treated liver explants. Conversely, hepatic lipase mRNA levels were increased 3.5-fold. ROSI, but not PIO, induced acetyl-CoA carboxylase and fatty acid synthase gene expression and increased apoB secretion suggesting a stimulation of lipogenesis. Concurrently, peroxisome proliferator-activated receptor-, mRNA levels were induced by ROSI and not significantly changed by PIO. Besides, PIO appeared to be a more potent activator of AMP-Activated Protein Kinase than ROSI. Conclusions PIO and ROSI exert specific direct effects on liver and extrapolating these data to humans could explain the significant improvements in plasma lipids observed in diabetic patients treated with PIO. Copyright © 2010 John Wiley & Sons, Ltd. [source] Statins inhibit NK-cell cytotoxicity by interfering with LFA-1-mediated conjugate formationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2009Patrick C. Raemer Abstract Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, commonly referred to as statins, are inhibitors of cholesterol biosynthesis. They are broadly used for treating hypercholesterolemia and for prevention of cardio- and cerebrovascular diseases. Recent publications show that statins also act as immunomodulatory drugs. Here, we show that lipophilic statins inhibit NK-cell degranulation and cytotoxicity. This effect was reversible by addition of substrates of isoprenylation, but not by addition of cholesterol. In NK-target cell conjugates intracellular Ca2+ flux was unaffected by statin treatment. However, statins strongly reduced the amount of conjugate formation between NK and target cells. This inhibition was paralleled by a statin-dependent inhibition of LFA-1-mediated adhesion and a reduction of NK-cell polarization. This demonstrates that statins impair the formation of effector,target cell conjugates resulting in the disruption of early signaling and the loss of NK-cell cytotoxicity. [source] Disruption of the gene encoding 3,-hydroxysterol ,14 -reductase (Tm7sf2) in mice does not impair cholesterol biosynthesisFEBS JOURNAL, Issue 20 2008Anna M. Bennati Tm7sf2 gene encodes 3,-hydroxysterol ,14 -reductase (C14SR, DHCR14), an endoplasmic reticulum enzyme acting on ,14 -unsaturated sterol intermediates during the conversion of lanosterol to cholesterol. The C-terminal domain of lamin B receptor, a protein of the inner nuclear membrane mainly involved in heterochromatin organization, also possesses sterol ,14 -reductase activity. The subcellular localization suggests a primary role of C14SR in cholesterol biosynthesis. To investigate the role of C14SR and lamin B receptor as 3,-hydroxysterol ,14 -reductases, Tm7sf2 knockout mice were generated and their biochemical characterization was performed. No Tm7sf2 mRNA was detected in the liver of knockout mice. Neither C14SR protein nor 3,-hydroxysterol ,14 -reductase activity were detectable in liver microsomes of Tm7sf2(,/,) mice, confirming the effectiveness of gene inactivation. C14SR protein and its enzymatic activity were about half of control levels in the liver of heterozygous mice. Normal cholesterol levels in liver membranes and in plasma indicated that, despite the lack of C14SR, Tm7sf2(,/,) mice are able to perform cholesterol biosynthesis. Lamin B receptor 3,-hydroxysterol ,14 -reductase activity determined in liver nuclei showed comparable values in wild-type and knockout mice. These results suggest that lamin B receptor, although residing in nuclear membranes, may contribute to cholesterol biosynthesis in Tm7sf2(,/,) mice. Affymetrix microarray analysis of gene expression revealed that several genes involved in cell-cycle progression are downregulated in the liver of Tm7sf2(,/,) mice, whereas genes involved in xenobiotic metabolism are upregulated. [source] Regulation of multidrug resistance 2 P-glycoprotein expression by bile salts in rats and in primary cultures of rat hepatocytesHEPATOLOGY, Issue 2 2000Seema Gupta Biliary phospholipid secretion is tightly coupled to the secretion of free cholesterol and bile salts. The secretion of phospholipids across the canalicular membrane of hepatocytes occurs via the multidrug resistance 2 (mdr2) P-glycoprotein (Pgp). The mechanism underlying the coupling of bile salt and phospholipid secretion has not been elucidated. The aims of this study were to determine the effects of bile acid structure on the expression of mdr2 in vitro and in vivo. Under optimal culture conditions, taurine-conjugated bile acids (50 ,mol/L) increased mdr2 messenger RNA (mRNA) levels in the following order: taurocholate (TCA) (288 ± 36%, P < .005) = taurodeoxycholate (TDCA) (276 ± 36%, P < .025) > taurochenodeoxycholate (TCDCA) (216 ± 34%, P < .025) > tauroursodeoxycholate (TUDCA) (175 ± 28%, P < .05) of control levels. The increase in mdr2 mRNA levels by TCA was both time and concentration dependent. Cholate feeding to rats with intact enterohepatic circulation increased mdr2 transcriptional activity by 4-fold and protein mass by 1.9-fold. Chronic biliary diversion (CBD) decreased mdr2 mRNA levels to 66 ± 9% (P < .025) of sham-operated controls. Intraduodenal infusion of TCA for 48 hours in CBD rats caused a significant increase in mdr2 mRNA levels (224%) as compared with CBD controls. A diet high in cholesterol (4%) decreased mdr2 mRNA levels to 57% ± 2 (P < .001) of pair-fed controls. Squalestatin (1 ,mol/L), an inhibitor of cholesterol biosynthesis, increased mdr2 mRNA levels by 8.8-fold (P < .005) in hepatocyte cultures after 24 hours. In conclusion, in the rat, bile acids up-regulated mdr2 transcriptional activity whereas cholesterol decreased mdr2 mRNA both in vitro and in vivo. [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] Inhibition of human squalene monooxygenase by selenium compoundsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 1 2002Nisha Gupta Abstract Selenosis in animals is characterized by a variety of neurological abnormalities, but the chemical species of selenium and the molecular targets that mediate this neurotoxicity are unknown. We have previously shown that selenite is a potent inhibitor of squalene monooxygenase, the second enzyme in the committed pathway for cholesterol biosynthesis; inhibition of this enzyme by dimethyltellurium leads to a peripheral demyelinating neuropathy similar to that seen in selenosis. To evaluate the role methylation plays in selenium toxicity, we examined the ability of three methylselenium compounds, methylselenol, dimethylselenide, and trimethylselenonium iodide, to inhibit purified recombinant human squalene monooxygenase. IC50 values for methylselenol (95 ,M) and dimethylselenide (680 ,M) were greater than that previously obtained for selenite (37 ,M), and inhibition by trimethylselenonium iodide was evident only at concentrations above 3 mM. Inhibition by methylselenol as well as by selenite was slow and irreversible, suggestive of covalent binding to the enzyme, and thiol-containing compounds could prevent and reverse this inhibition, indicating that these compounds were reacting with sulfhydryl groups on the protein. Monothiols such as glutathione and ,-mercaptoethanol provided better protection than did dithiols, suggesting that these selenium compounds bind to only one of the two proposed vicinal cysteines on squalene monooxygenase. Unexpectedly, the inhibition by selenite was significantly enhanced by dithiols, indicating that a more toxic species, possibly selenide, was formed in the presence of these dithiol reductants. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:18,23, 2002; DOI 10.1002/jbt.10014 [source] Insulin-like growth factor-I-stimulated Akt phosphorylation and oligodendrocyte progenitor cell survival require cholesterol-enriched membranesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 15 2009Robert J. Romanelli Abstract Previously we showed that insulin-like growth factor-I (IGF-I) promotes sustained phosphorylation of Akt in oligodendrocyte progenitor cells (OPCs) and that Akt phosphorylation is required for survival of these cells. The direct mechanisms, however, by which IGF-I promotes Akt phosphorylation are currently undefined. Recently, cholesterol-enriched membranes (CEMs) have been implicated in regulation of growth factor-mediated activation of the PI3K/Akt pathway and survival of mature oligodendrocytes; however, less is know about their role in OPC survival. In the present study, we investigate the role of CEMs in IGF-I-mediated Akt phosphorylation and OPC survival. We report that acute disruption of membrane cholesterol with methyl-,-cyclodextrin results in altered OPC morphology and inhibition of IGF-I-mediated Akt phosphorylation. We also report that long-term inhibition of cholesterol biosynthesis with 25-hydroxycholesterol blocks IGF-I stimulated Akt phosphorylation and cell survival. Moreover, we show that the PI3K regulatory subunit, p85, Akt, and the IGF-IR are sequestered within cholesterol-enriched fractions in steady-state stimulation of the IGF-IR and that phosphorylated Akt and IGF-IR are present in cholesterol-enriched fractions with IGF-I stimulation. Together, the results of these studies support a role for CEMs or "lipid rafts" in IGF-I-mediated Akt phosphorylation and provide a better understanding of the mechanisms by which IGF-I promotes OPC survival. © 2009 Wiley-Liss, Inc. [source] Chronic Alcohol Consumption Disrupted Cholesterol Homeostasis in Rats: Down-Regulation of Low-Density Lipoprotein Receptor and Enhancement of Cholesterol Biosynthesis Pathway in the LiverALCOHOLISM, Issue 3 2010Zhigang Wang Background:, Chronic alcohol consumption causes alcoholic liver disease, which is associated, or initiated, with dysregulated lipid metabolism. Very recent evidence suggested that dysregulated cholesterol metabolism plays an important role in the pathogenesis of alcoholic fatty liver diseases, however, the effects of chronic alcohol exposure on cholesterol homeostasis have not been well studied and underlying mechanisms behind are still elusive. Methods:, Male Sprague,Dawley rats weighing 250 ± 5.5 g (mean ± SEM) divided into 2 groups (8 rats per group) and pair-fed with liquid diets containing (in percent of energy intake) 18% protein, 35% fat, 12% carbohydrate, and 35% either ethanol (ethanol diet) or an isocaloric maltose-dextrin mixture (control diet), according to Lieber and De Carli, for 4 weeks. Results:, Long-term excessive alcohol feeding to rats caused fatty liver and liver injury, which was associated with disrupted cholesterol homeostasis, characterized by increased hepatic cholesterol levels and hypercholesterolemia. Hepatic cholesterol increases were concomitant with constantly activated sterol regulatory element-binding protein-2 (SREBP-2) in the liver and increased expression of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme for cholesterol de novo synthesis, indicating enhanced cholesterol biosynthesis. Alcohol-induced hypercholesterolemia was accompanied by decreased LDL receptor (LDLr) levels in the liver. Further investigations revealed that chronic alcohol exposure increased hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) contents to down-regulate LDLr via a post-translational mechanism. Moreover, alcohol feeding suppressed extracellular signal-regulated kinase (ERK) activation in the liver. In vitro studies showed that inhibition of ERK activation was associated with decreased LDLr expression in HepG2 cells. Conclusions:, Our study provides the first evidence that both increased PCSK9 expression and suppressed ERK activation in the liver contributes to alcohol-induced hypercholesterolemia in rats. [source] Role of Policosanols in the Prevention and Treatment of Cardiovascular DiseaseNUTRITION REVIEWS, Issue 11 2003Krista A. Varady BASc Policosanols are a mixture of aliphatic alcohols derived from purified sugar cane. When administered at 5 to 20 mg/day, policosanols have been shown to decrease the risk of atheroma formation by reducing platelet aggregation, endothelial damage, and foam cell formation in animals. Additionally, policosanols have been shown to lower total and low-density lipoprotein (LDL) cholesterol levels by 13 to 23% and 19 to 31%, respectively, while increasing high-density lipoprotein (HDL) cholesterol from 8 to 29%. Policosanols are thought to improve lipid profiles by reducing hepatic cholesterol biosynthesis while enhancing LDL clearance. When compared with statins, policosanols exhibit comparable cholesterol-lowering effects at much smaller doses. The mixture is well tolerated when administered to animals; however, a more precise safety profile is needed for humans. In summary, policosanols are a promising resource in the prevention and therapy of cardiovascular disease (CVD), but these results need to be confirmed in independent laboratories. [source] Abnormal sterol metabolism in holoprosencephaly,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Dorothea Haas Abstract Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans. The HPE phenotype is extremely variable and the etiology is heterogeneous. Among a variety of embryological toxins that can induce HPE, inhibitors, and other pertubations of cholesterol biosynthesis have been shown to be important factors, most likely because cholesterol is required in the Sonic hedgehog signaling cascade. Decreased levels of maternal cholesterol during pregnancy increase the risk for preterm delivery, but they are not associated with congenital malformations. However, if the fetus is affected by an inborn error of endogenous cholesterol synthesis, a reduction of maternal cholesterol concentration and cholesterol transport over the placenta aggravates the phenotypic expression. Exposure to lipophilic statins in early pregnancy may be associated with a substantial risk for structural CNS defects. © 2010 Wiley-Liss, Inc. [source] Smith-Lemli-Opitz syndrome: New mutation with a mild phenotypeAMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2002Chitra Prasad Abstract Smith-Lemli-Opitz syndrome (SLOS) (Online Mendelian Inheritance in Man, OMIMÔ, 2001, http://www.ncbi.nlm.nih.gov/omim/ for SLOS, MIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 3,-hydroxysterol ,7 -reductase gene, DHCR7. We report on a female infant with an exceptionally mild phenotype of SLOS, in whom molecular studies identified a new mutation in DHCR7. The proposita initially presented with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2,3 syndactyly of her toes in both feet. The plasma cholesterol was borderline low at 2.88 mmol/L (normal 2.97,4.40 mmol/L). Elevated plasma 7-dehydrocholesterol level of 200.0 ,mol/L confirmed the clinical diagnosis of SLOS. Molecular analysis demonstrated compound heterozygosity for IVS8-1G ,C and Y280C, a new missense mutation in DHCR7. Since the other mutation in this patient is a known null mutation, this newly discovered mutation is presumably associated with significant residual enzyme activity and milder expression of clinical phenotype. © 2002 Wiley-Liss, Inc. [source] Specific congenital heart defects in RSH/Smith-Lemli-Opitz syndrome: Postulated involvement of the Sonic Hedgehog pathway in syndromes with postaxial polydactyly or heterotaxiaBIRTH DEFECTS RESEARCH, Issue 3 2003Maria Cristina Digilio BACKGROUND RSH/Smith-Lemli-Opitz syndrome is an autosomal recessive syndrome due to an inborn error of cholesterol metabolism and is characterized by developmental delay, facial anomalies, hypospadias, congenital heart defect (CHD), postaxial polydactyly, and 2,3 toe syndactyly. CHD is found in half of the propositi, and a specific association with atrioventricular canal defect (AVCD) and anomalous pulmonary venous return has been demonstrated. METHODS We report on an additional patient with RSH/SLOS presenting with complete AVCD and anomalous pulmonary venous return, and discuss the possible relationship of the Sonic Hedgehog (SHH) pathway as causative factor of these CHDs and those in heterotaxia patients with postaxial polydactyly syndromes. RESULTS Anatomic similarities between heterotaxia and CHDs of several syndromes with postaxial polydactyly have been noted previously, considering the frequent association of AVCD with common atrium in these conditions. It is known that both CHDs of heterotaxia and postaxial polydactyly can be related to abnormalities of the SHH pathway. Cholesterol has a critical role in the formation of normally active hedgehog proteins. It could be hypothesized that specific types of CHDs in RSH/SLOS can be caused by modifications of the SHH protein related to the defect of cholesterol biosynthesis. CONCLUSIONS The specific association of AVCD and anomalous pulmonary venous return in patients with RSH/SLOS and the finding of AVCD ± common atrium in several syndromes with polydactyly leads to the hypothesis that heterotaxia due to SHH anomalies could be involved in a large spectrum of conditions. Perturbations in different components of the SHH pathway could lead to several developmental errors presenting with partially overlapping clinical manifestations. Birth Defects Research (Part A) 67149,153, 2003. © 2003 Wiley-Liss, Inc. [source] Apolipoprotein E and apolipoprotein B genotypes and risk for spina bifidaBIRTH DEFECTS RESEARCH, Issue 5 2002Kelly A. Volcik Background Altered cholesterol metabolism and defects in cholesterol biosynthesis may influence abnormal central nervous system (CNS) development. During early stages of embryonic development, high levels of cholesterol are needed by rapidly proliferating cells that utilize cholesterol as a key cell membrane component. Alterations in cholesterol levels are influenced by variations in the apolipoprotein E (apoE) and apolipoprotein B (apoB) genes. The purpose of our study was to explore the possible association between infant genetic variations in the apoE and apoB genes and spina bifida (SB) risk. Methods Genomic DNA was extracted from newborn screening blood spots obtained from 26 infants with SB and 73 non-malformed control infants. ApoE and apoB genotypes were determined by restriction enzyme digestion of PCR amplification products. Results Genotype frequencies for the apoE and apoB polymorphisms were not statistically different between case and control infants. For each apoB polymorphism, however, the frequency of the wild-type allele was higher in SB infants as compared to controls. Additionally, the apoE genotype E2/E3 was observed more frequently in the controls than in SB infants [15% in controls compared to 4% in cases; OR = 0.2 (0,1.6)]. Conclusions Results from this study suggest that genetic variations in the apoE and apoB genes, known to regulate cholesterol metabolism, do not substantially contribute to the risk of SB in infants. Teratology 66:257,259, 2002. © 2002 Wiley-Liss, Inc. [source] Simvastatin inactivates ,1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cellsCANCER SCIENCE, Issue 6 2007Ikuko Takeda The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, also called statins, are commonly used as lipid-lowering drugs that inhibit cholesterol biosynthesis. An anticancer effect, as a pleiotropic function of certain statins, has been hypothesized. In the present study, we investigated the effect of simvastatin, one of the natural statins, on cell proliferation, cell cycle, invasive activity, and molecular expressions associated with cell,extracellular matrix adhesion, signal transduction, and DNA synthesis in Tu167 and JMAR cells from head and neck squamous cell carcinoma. The addition of simvastatin resulted in a dose-dependent inhibition of cell growth and migration into the extracellular matrix. Considerable morphological changes occurred after treatment with simvastatin, demonstrating loss of cell adhesion and disruption of actin filaments in cytoplasm. The inhibitory effect of simvastatin on cell proliferation seemed to be associated with cell cycle arrest and increased expression of p21, p27, and activated caspase-3. The expression of ,1-integrin, a counter adhesion for the extracellular matrix, phosphorylated FAK, and phosphorylated ERK was decreased by treatment with simvastatin. The proapoptotic effect of simvastatin was inhibited by treatment with mevalonate. cDNA microarray assay demonstrated that molecular changes resulting from treatment with simvastatin included the up-regulation of cell cycle regulators and apoptosis-inducing factors and the down-regulation of integrin-associated molecules and cell proliferation markers. Of down-regulated genes induced by simvastatin treatment, a significant depletion of thymidylate synthase was confirmed using western blot analysis. These results imply that simvastatin has the potential to be effective for the prevention of the growth and metastasis of cancer cells. (Cancer Sci 2007; 98: 890,899) [source] | ||||||||||||||||