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Gustav Dallner - One of the best experts on this subject based on the ideXlab platform.
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Effects of Mevinolin treatment on tissue dolichol and ubiquinone levels in the rat
Biochimica et biophysica acta, 1992Co-Authors: Peter Löw, Magnus Andersson, Conny Edlund, Gustav DallnerAbstract:Rats were treated with Mevinolin by intraperitoneal injection (15 days) or dietary administration (30 days). The cholesterol, dolichol, dolichyl phosphate and ubiquinone contents of the liver, brain, heart, muscle and blood were then investigated. The cholesterol contents of these organs did not change significantly, with the exception of muscle. Intraperitoneal administration of the drug increases the amount of dolichol in liver, muscle and blood and decreases the dolichyl-P amount in muscle. The same treatment increases the level of ubiquinone in muscle and blood and decreases this value in liver and heart. Oral administration decreases dolichol, dolichyl-P and ubiquinone levels in heart and muscle, while in liver the dolichol level is elevated and ubiquinone level lowered. In brain the amount of dolichyl-P is increased. Intraperitoneal injection of Mevinolin also modifies the liver dolichol and dolichyl-P isoprenoid pattern, with an increase in shorter chain polyisoprenes. The levels of dolichol and ubiquinone in the blood do not follow the changes observed in other tissues. Incorporation of [3H]acetate into cholesterol by liver slices prepared from Mevinolin-treated rats exhibited an increase, whereas in brain no change was seen. Labeling of dolichol and ubiquinone was increased in both liver and brain, but incorporation into dolichyl phosphate remained relatively stable. The results indicate that Mevinolin affects not only HMG-CoA reductase but, to some extent, also affects certain of the peripheral enzymes, resulting in considerable effects on the various mevalonate pathway lipids.
E. F. Stange - One of the best experts on this subject based on the ideXlab platform.
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Mevinolin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, suppresses enterocyte esterification of exogenous but not endogenous cholesterol.
Biochimica et biophysica acta, 1992Co-Authors: Klaus Fellermann, Frank M. Reimann, Gerhard Herold, E. F. StangeAbstract:Mevinolin (lovastatin), a competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase, directly inhibited acyl-CoA cholesteryl acyltransferase in rabbit intestinal microsomes at a dose of 20 micrograms/ml or more. Lineweaver-Burk analysis showed a competitive type of inhibition with respect to oleoyl-CoA. In cultured intestinal Caco-2 cells, Mevinolin reduced [14C]oleate incorporation into cholesteryl-esters by 86% of controls at doses as low as 0.1 micrograms/ml. However, in cells whose activity of acyl-CoA cholesteryl acyltransferase was stimulated 7-fold by 10 mM mevalonolactone, a significant inhibitory effect on cholesteryl-ester formation could not be detected, even at 40 micrograms/ml of Mevinolin. In contrast, cells supplied with liposomal cholesterol or cholesterol derived from low-density lipoproteins showed a marked reduction of cholesteryl-ester formation in the presence of 10 or 0.1 micrograms/ml of Mevinolin, respectively. It is concluded that the observed suppressive effects of Mevinolin on cholesterol esterification in cultured Caco-2 cells are indirect and possibly caused by changes in the acyl-CoA cholesteryl acyltransferase substrate pool or intracellular cholesterol transport.
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Compartmentalization of cholesterol metabolism and cellular growth in cultured intestinal crypt cells
Biochimica et biophysica acta, 1991Co-Authors: Frank M. Reimann, Gerhard Herold, A. Schneider, E. F. StangeAbstract:Growth of rat intestinal crypt derived cells IEC-6 ceased when the key enzyme of cholesterol synthesis, hydroxymethylglutaryl-CoA reductase, was blocked by the competitive inhibitor Mevinolin. This effect was reversed by the addition of mevalonolactone. LDL suppressed reductase activity as well as cholesterol synthesis from [14C]octanoate and stimulated acyl-CoA cholesterol acyltransferase, but failed to support cell growth despite rapid receptor mediated degradation even in the presence of low mevalonolactone concentrations. Inhibition of cholesterol esterification by Sandoz-Compound 58-035 enhanced cell growth in the presence of Mevinolin, but did not promote proliferation in the additional presence of low-density lipoproteins. HDL3 but not HDL2 or tetranitromethane-modified HDL3 totally reversed the Mevinolin induced inhibition of cell growth. This rescue by HDL3 was overcome by an increased dose of Mevinolin. HDL3 derepressed reductase, stimulated cholesterol synthesis and reduced cholesterol esterification, but did not reverse the cholesterol synthesis inhibition by Mevinolin. It is concluded that IEC-6 cells preferentially use endogenously synthesized cholesterol for membrane formation rather than low-density lipoprotein cholesterol. High-density lipoproteins appear to normalize cell growth in the presence of Mevinolin by inhibition of cholesterol esterification and probably by inducing the formation of non sterol products of mevalonate.
W F Doolittle - One of the best experts on this subject based on the ideXlab platform.
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Mevinolin-resistant mutations identify a promoter and the gene for a eukaryote-like 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the archaebacterium Haloferax volcanii.
The Journal of biological chemistry, 1992Co-Authors: W L Lam, W F DoolittleAbstract:Abstract Both eukaryotes and archaebacteria use 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase to synthesize mevalonate, which eukaryotes employ in the production of sterols and archaebacteria need for the isoprenoid side chains of their unique and characteristic lipids. The drug Mevinolin inhibits HMG-CoA reductase in eukaryotes and in the halophilic archaebacteria, and we have used a spontaneous mutation to Mevinolin resistance in the construction of a selectable shuttle vector for Haloferax volcanii. Sequence analysis shows that this resistance determinant encodes an HMG-CoA reductase very like its eukaryotic homologs, but sharing with the one sequenced eubacterial HMG-CoA reductase (that of Pseudomonas mevalonii) few residues other than those common to all HMG-CoA reductases. Characterization of several spontaneous Mevinolin-resistant mutants reveals that they are of two sorts: amplifications of the HMG-CoA reductase gene with varying amounts of flanking sequence, and point mutants upstream of the HMG-CoA reductase coding region. We compared sequence and expression of a mutant gene of the latter class to those of the wild-type gene. The point mutation found affects the TATA box-like "distal promoter element," results (like gene amplification) in resistance through the synthesis of excess gene product, and provides the first true genetic definition of an archaebacterial promoter.
Peter Löw - One of the best experts on this subject based on the ideXlab platform.
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Effects of Mevinolin treatment on tissue dolichol and ubiquinone levels in the rat
Biochimica et biophysica acta, 1992Co-Authors: Peter Löw, Magnus Andersson, Conny Edlund, Gustav DallnerAbstract:Rats were treated with Mevinolin by intraperitoneal injection (15 days) or dietary administration (30 days). The cholesterol, dolichol, dolichyl phosphate and ubiquinone contents of the liver, brain, heart, muscle and blood were then investigated. The cholesterol contents of these organs did not change significantly, with the exception of muscle. Intraperitoneal administration of the drug increases the amount of dolichol in liver, muscle and blood and decreases the dolichyl-P amount in muscle. The same treatment increases the level of ubiquinone in muscle and blood and decreases this value in liver and heart. Oral administration decreases dolichol, dolichyl-P and ubiquinone levels in heart and muscle, while in liver the dolichol level is elevated and ubiquinone level lowered. In brain the amount of dolichyl-P is increased. Intraperitoneal injection of Mevinolin also modifies the liver dolichol and dolichyl-P isoprenoid pattern, with an increase in shorter chain polyisoprenes. The levels of dolichol and ubiquinone in the blood do not follow the changes observed in other tissues. Incorporation of [3H]acetate into cholesterol by liver slices prepared from Mevinolin-treated rats exhibited an increase, whereas in brain no change was seen. Labeling of dolichol and ubiquinone was increased in both liver and brain, but incorporation into dolichyl phosphate remained relatively stable. The results indicate that Mevinolin affects not only HMG-CoA reductase but, to some extent, also affects certain of the peripheral enzymes, resulting in considerable effects on the various mevalonate pathway lipids.
Joseph L. Goldstein - One of the best experts on this subject based on the ideXlab platform.
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Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholeserolemia heterozygotes. 1983.
Atherosclerosis. Supplements, 2004Co-Authors: David W. Bilheimer, Scott M. Grundy, Michael S. Brown, Joseph L. GoldsteinAbstract:In subjects with heterozygous familial hypercholesterolemia (FH), a 50% deficiency of receptors for plasma low density lipoprotein (LDL) impairs the removal of LDL from plasma and produces hypercholesterolemia. In these patients Mevinolin, an inhibitor of 3-hydroi[y-3-methylglutaryl-CoA reductase, blocks dldenternlsynthesis and lowers plasma LDL levels. To determine the mechanism for the LDL-kmcring effect, we administered 131 I-labeled LDL intravenously to six FH heterozygotes before and during treatment with Mevinolin and calculated the apparent fractional catabolic rote (FCR) and synthetic rate for LDL. After Mevinolin treatment, the mean plasma LDL-chnlesterol level dedined from 262 to 191 mg/dl (27% decrease), the mean FCR for 131 I-labeled LDL increased from 0.30 to 0.41 pools per day (37% increase), and the mean calculated synthetic rate for LDL-protein did not change significantly. In one FH heterozygote with an lieal bypass and in another who received colestipol, the addition of Mevinolin caused, respectively, a 41% and 60% decrease in plasma LDL levels and a 60% and 100% increase in the FCR for plasma LDL. The contribution of receptor-dependent pathways to the FCR for plasma LDL was estimated in three FH heterozygotes by simultaneous measurements of the FCR for native 131 I-labeled LDL and 125 I-labeld glucosylated LDL, which does not bind to LDL receptors. Whereas the removal rate for native LDL increased after Mevinolin treatment, the removal rate for glucosylated LDL did not change. The corrent data suggest that Mevinolin alone or Mevinolin plus bile acid depletion (i.e., ileal bypass or colestipol therapy) decreases plasma LDL levels primarily by raising the number of LDL receptors and, thus, enhancing the removal of LDL from plasma.