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Resveratrol potentiates effect of simvastatin on inhibition of mevalonate pathway in human endometrial stromal cells.
Villanueva JA, Sokalska A, Cress AB, Ortega I, Bruner-Tran KL, Osteen KG, Duleba AJ
(2013) J Clin Endocrinol Metab 98: E455-62
MeSH Terms: Acetates, Adult, Anti-Inflammatory Agents, Non-Steroidal, Carbon Radioisotopes, Cholesterol, Drug Synergism, Endometrium, Female, Gene Expression Regulation, Enzymologic, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mevalonic Acid, Primary Cell Culture, RNA, Messenger, Resveratrol, Simvastatin, Stilbenes, Stromal Cells
Show Abstract · Added May 29, 2014
CONTEXT - Growth of endometriotic lesions in rodent model of endometriosis is inhibited by resveratrol, a natural polyphenol with antiproliferative and antiinflammatory properties, and simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) activity.
OBJECTIVE - The objective of the investigation was to study the mechanism of action of resveratrol and its interactions with simvastatin, focusing on cholesterol biosynthesis and HMGCR gene expression and protein activity in primary cultures of human endometrial stromal (HES) cells.
METHODS - HES cells were obtained from healthy volunteers. Biosynthesis of cholesterol was assessed by measuring the conversion of [(14)C]acetate to [(14)C]cholesterol. HMGCR mRNA transcripts were quantified by real-time PCR, protein expression by Western blot analysis, and enzyme activity by measuring the conversion of [3-(14)C]3-hydroxy-3-methyl-glutaryl-coenzyme A to [(14)C]mevalonic acid lactone in HES cell microsomes.
RESULTS - Resveratrol inhibited cholesterol biosynthesis, HMGCR mRNA, and enzyme activity. Simvastatin inhibited cholesterol biosynthesis and enzyme activity but increased HMGCR mRNA and protein expression. Resveratrol potentiated the inhibitory effects of simvastatin on cholesterol biosynthesis and HMGCR enzyme activity and abrogated the stimulatory effects of simvastatin on HMGCR mRNA transcripts and protein expression.
CONCLUSIONS - Resveratrol inhibits key steps of the mevalonate pathway by mechanisms that are partly complementary to and partly comparable with simvastatin via reducing both expression and activity of HMGCR. A combination of resveratrol and simvastatin may be of potential clinical relevance to development new treatments of human endometriosis.
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19 MeSH Terms
Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction.
Hao M, Head WS, Gunawardana SC, Hasty AH, Piston DW
(2007) Diabetes 56: 2328-38
MeSH Terms: Animals, Cell Survival, Cholesterol, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Glucokinase, Glucose, Humans, Hyperlipidemias, Insulin, Insulin Secretion, Insulin-Secreting Cells, Islets of Langerhans, Mevalonic Acid, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase Type I
Show Abstract · Added March 27, 2013
OBJECTIVE - Type 2 diabetes is often accompanied by abnormal blood lipid and lipoprotein levels, but most studies on the link between hyperlipidemia and diabetes have focused on free fatty acids (FFAs). In this study, we examined the relationship between cholesterol and insulin secretion from pancreatic beta-cells that is independent of the effects of FFAs.
RESEARCH DESIGN AND METHODS - Several methods were used to modulate cholesterol levels in intact islets and cultured beta-cells, including a recently developed mouse model that exhibits elevated cholesterol but normal FFA levels. Acute and metabolic alteration of cholesterol was done using pharmacological reagents.
RESULTS - We found a direct link between elevated serum cholesterol and reduced insulin secretion, with normal secretion restored by cholesterol depletion. We further demonstrate that excess cholesterol inhibits secretion by downregulation of metabolism through increased neuronal nitric oxide synthase dimerization.
CONCLUSIONS - This direct effect of cholesterol on beta-cell metabolism opens a novel set of mechanisms that may contribute to beta-cell dysfunction and the onset of diabetes in obese patients.
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18 MeSH Terms
Purification and properties of a palmitoyl-protein thioesterase that cleaves palmitate from H-Ras.
Camp LA, Hofmann SL
(1993) J Biol Chem 268: 22566-74
MeSH Terms: Amino Acid Sequence, Animals, Baculoviridae, Base Sequence, Chromatography, Affinity, Chromatography, Gel, Chromatography, High Pressure Liquid, Chromatography, Ion Exchange, Female, Gene Transfer Techniques, Guanine Nucleotides, Kinetics, Magnesium, Male, Mevalonic Acid, Molecular Sequence Data, Molecular Weight, Moths, Oligodeoxyribonucleotides, Oncogene Protein p21(ras), Palmitic Acid, Palmitic Acids, Palmitoyl-CoA Hydrolase, Protein Processing, Post-Translational, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 5, 2014
H-Ras, the protein product of the cellular homologue of the Harvey ras oncogene, undergoes a complex series of post-translational modifications that include C-terminal isoprenylation, proteolysis, methylation, and palmitoylation. Palmitoylation has been shown to enhance the transformation efficiency of H-Ras about 10-fold in vivo. A recent study (Magee, A. I., Gutierrez, L., McKay, I. A., Marshall, C. J., and Hall, A. (1987) EMBO J. 6, 3353-3357) has provided strong evidence that the palmitate undergoes a dynamic acylation-deacylation cycle, but details concerning the enzymology of this process and its regulation are lacking. To begin to dissect this event, we have developed an assay for the enzymatic removal of palmitate from [3H]palmitate-labeled H-Ras. This substrate was produced in a baculovirus expression system and was used to purify to homogeneity a novel 37-kDa enzyme from bovine brain cytosol that removes the radiolabeled palmitate. The purified enzyme is sensitive to diethyl pyrocarbonate and insensitive to phenylmethylsulfonyl fluoride and N-ethylmaleimide. Interestingly, the thioesterase recognizes H-Ras as a substrate only when H-Ras is in its native conformation (bound to Mg2+ and guanine nucleotide). The palmitoylated alpha subunits of the heterotrimeric G proteins are also substrates for the enzyme.
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26 MeSH Terms
Impaired renal mevalonate metabolism in nephrotic syndrome: a stimulus for increased hepatic cholesterogenesis independent of GFR and hypoalbuminemia.
Golper TA, Swartz SH
(1982) Metabolism 31: 471-6
MeSH Terms: Animals, Cholesterol, Glomerular Filtration Rate, Inulin, Kidney, Liver, Male, Mevalonic Acid, Nephrotic Syndrome, Puromycin Aminonucleoside, Rats, Rats, Inbred Strains, Serum Albumin, Sodium
Show Abstract · Added August 10, 2015
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.
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14 MeSH Terms
The role of circulating mevalonate in nephrotic hypercholesterolemia in the rat.
Golper TA, Feingold KR, Fulford MH, Siperstein MD
(1986) J Lipid Res 27: 1044-51
MeSH Terms: Animals, Cholesterol, Female, Hydroxymethylglutaryl CoA Reductases, Hypercholesterolemia, In Vitro Techniques, Liver, Mevalonic Acid, Nephrotic Syndrome, Rats, Rats, Inbred Strains
Show Abstract · Added August 10, 2015
The cause of the hypercholesterolemia that characterizes the nephrotic syndrome has never been adequately explained. The present study examines the possibility that enhanced availability of the cholesterol precursor, mevalonic acid, to the liver in the nephrotic state may result in increased hepatic cholesterogenesis. In normal animals, the kidneys are known to be the major site of the metabolism of circulating mevalonate to both cholesterol and CO2. Previous studies, using perfusion of isolated, intact kidneys, have shown that the excretion and metabolism of mevalonate are both impaired in nephrosis. The present investigation has demonstrated in vivo that puromycin aminonucleoside nephrosis results in a 25% reduction in the oxidation of mevalonate to CO2. In the same nephrotic animals, cholesterogenesis from circulating mevalonate was significantly increased in both liver and carcass. In addition, liver slices from nephrotic animals incorporated increased amounts of [5-14C]mevalonate into cholesterol when calculated per whole liver, but not per gram of liver. Oxidation of mevalonic acid by kidney slices was significantly reduced, whether expressed as per gram of tissue or per whole organ. HMG-CoA (3-hydroxy-3-methylglutaryl) reductase activity in liver of nephrotic animals was significantly increased. We conclude that, in the nephrotic state, impaired mevalonate metabolism by the kidney may contribute to enhanced cholesterogenesis by increasing delivery of mevalonate to liver and carcass; in addition, nephrosis appears to provide an undefined stimulus for HMG-CoA reductase activity in the liver, thereby providing an additional enhancement of hepatic cholesterogenesis.
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11 MeSH Terms
Inhibition of pancreatic adenocarcinoma cell growth by lovastatin.
Sumi S, Beauchamp RD, Townsend CM, Uchida T, Murakami M, Rajaraman S, Ishizuka J, Thompson JC
(1992) Gastroenterology 103: 982-9
MeSH Terms: Animals, Cell Division, Cell Survival, Cricetinae, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, In Vitro Techniques, Lovastatin, Mevalonic Acid, Mice, Mice, Nude, Pancreatic Neoplasms, Time Factors, Transplantation, Heterologous, Tumor Cells, Cultured
Show Abstract · Added May 3, 2013
RAS protein (p21 ras) requires farnesyl (an intermediate of cholesterol synthesis) for activation. Activating mutations of K-ras gene have been detected in most human pancreatic adenocarcinomas. In the present study, the effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, the rate-limiting enzyme of cholesterol synthesis, on the growth of five pancreatic cancer cell lines (human-CAV, MIA Paca2, CAPAN2 and PANC1, and hamster-H2T) in vitro and of two cell lines (CAV and H2T) in vivo was examined. Inhibition of cell growth was observed with lovastatin doses at or above 2.5 micrograms/mL for H2T, CAV, MIA Paca2, and CAPAN2 or 10 micrograms/mL in PANC1. The H2T cell line was studied further to determine the reversibility of growth inhibition. Mevalonic acid (1 mmol/L) reversed lovastatin-induced inhibition of cell growth if it was added with lovastatin (2.5 micrograms/mL). Similarly, removal of lovastatin from the medium within 24 hours after treatment allowed recovery of cell growth. The effect of lovastatin on cell growth was irreversible after 48 hours of exposure. The survival fraction of H2T cells was markedly decreased by 1- or 24-hour exposure to 75 micrograms/mL but not to doses ranging from 0.5 to 60 micrograms/mL of lovastatin. Growth of pancreatic carcinoma xenografts (CAV and H2T) in nude mice was inhibited by a subcutaneous infusion of lovastatin (50 micrograms/h). These results indicate that mevalonic acid or a metabolite in the cholesterol synthesis pathway is necessary for growth of pancreatic cancer cells and suggest that lovastatin should be further examined as a potential therapeutic agent for pancreatic cancer.
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16 MeSH Terms