ubiquinone and mevastatin

Digoxin and ouabain are steroid drugs that inhibit the Na(+)/K(+)-ATPase, and are widely used in the treatment of heart diseases. They may also have additional effects, such as on metabolism of steroid hormones, although until now no evidence has been provided about the effects of these cardioactive glycosides on the synthesis of cholesterol. Here we report that digoxin and ouabain increased the synthesis of cholesterol in human liver HepG2 cells, enhancing the activity and the expression of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of the cholesterol synthesis. This effect was mediated by the binding of the sterol regulatory element binding protein-2 (SREBP-2) to the HMGCR promoter, and was lost in cells silenced for SREBP-2 or loaded with increasing amounts of cholesterol. Digoxin and ouabain competed with cholesterol for binding to the SREBP-cleavage-activating protein, and are critical regulators of cholesterol synthesis in human liver cells.

Topics: Cardiotonic Agents; Cholesterol; Digoxin; Enzyme Inhibitors; Hepatocytes; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Ouabain; Sterol Regulatory Element Binding Protein 2; Ubiquinone

Statins, inhibitors of hydroxymethylglutaryl-CoA reductase, reduce the intracellular synthesis of cholesterol and prevent the onset of atherosclerosis. They also decrease the synthesis of isoprenoid molecules, such as the side chain of ubiquinone and geranylgeranyl pyrophosphate. As a consequence, statins impair mitochondrial metabolism and the activation of small monomeric GTPases (such as Rho and Ras), causing toxic effects. To date, a successful strategy to prevent statin toxicity is lacking.. In human monocytic THP-1 cells, we measured the synthesis of cholesterol and isoprenoids, mitochondrial electron flow, the activity of RhoA and Rac, cell death and proliferation.. Mevastatin reduced the synthesis of cholesterol, geranylgeranyl pyrophosphate and ubiquinone, mitochondrial electron transport, activity of RhoA and Rac, and cell proliferation, accompanied by increased cell death. Geranylgeraniol, a cell-permeable analogue of geranylgeranyl pyrophosphate, reversed all these effects of mevastatin, without affecting its ability to reduce cholesterol synthesis. Notably, geranylgeraniol was more effective than the addition of exogenous ubiquinone, which rescued mitochondrial respiratory activity and reversed mevastatin cytotoxicity, but did not alter the decrease in cell proliferation. The same results were obtained in human liver HepG2 cells.. Geranylgeraniol had a broader protective effect against the cytotoxicity of statins than exogenous ubiquinone. Therefore, geranylgeraniol may be a more useful and practical means of limiting the toxicities of statins, without reducing their efficacy as cholesterol lowering agents.

Topics: Cell Death; Cell Line, Tumor; Cell Proliferation; Cholesterol; Diterpenes; Electron Transport; Hep G2 Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Mitochondria; Monocytes; Terpenes; Ubiquinone

Topics: Anticholesteremic Agents; Coenzymes; History, 20th Century; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Lipoproteins; Lovastatin; Ubiquinone

Topics: Acute Disease; Cell Division; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukemia, Myeloid; Lovastatin; Myelodysplastic Syndromes; Tumor Cells, Cultured; Ubiquinone

We report the ability of Giardia lamblia to modify several of its cellular proteins by isoprenylation. Trophozoites cultured in the presence of [3H]mevalonate synthesized radiolabeled proteins of approx. 50 and 21-26 kDa. Chemical analysis indicated that farnesyl and geranylgeranyl isoprenoids comprised the majority of the radiolabel covalently associated with trophozoite proteins. In addition, antibodies to human p21ras immunoprecipitated mevalonate-labelled species of approx. 21 kDa. Inhibitors of several enzymatic steps of the mevalonate pathway dramatically affected Giardia metabolism. Protein isoprenylation and cell growth were blocked by compactin and mevinolin, competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in isoprenoid biosynthesis. In the presence of these inhibitors, Giardia growth was restored by the addition of mevalonate to the culture medium. In contrast, cell growth was blocked irreversibly by inhibitors of subsequent steps in the protein isoprenylation pathway. Trophozoite growth inhibition by limonene, perillic acid, perillyl alcohol and N-acetyl-S-farnesyl-L-cysteine was not reversed after the addition of mevalonate, dolichol, ubiquinone or cholesterol to the medium. These observations constitute the first description of protein isoprenylation in any protozoan and indicate that this post-translational modification is an important step in the regulation of the growth of this primitive eukaryote.

Topics: Acetylcysteine; Animals; Cholesterol; Cyclohexenes; Dolichols; Giardia lamblia; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Limonene; Lipid Metabolism; Lovastatin; Mevalonic Acid; Monoterpenes; Protein Prenylation; Proto-Oncogene Proteins p21(ras); Protozoan Proteins; Terpenes; Ubiquinone

We studied the effects of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on serum levels of lipoproteins and ubiquinone-10-in seven heterozygous patients with familial hypercholesterolemia. ML-236B was given at doses of 30 to 60 mg per day for 24 weeks. Serum cholesterol decreased from 390 +/- 9 to 303 +/- 8 mg per deciliter (101 +/- 0.2 to 7.88 +/- 0.2 mmol per liter, mean +/- S.E.M.; p less than 0.001) and serum triglyceride decreased from 137 +/- 18 to 87 +/- 9 mg per deciliter (1.55 +/- 0.20 to 0.98 +/- 0.01 mmol per liter; p less than 0.05). Intermediate-density-lipoprotein (DL) cholesterol, IDL triglyceride, low-density-lipoprotein (LDL) cholesterol, and LDL triglyceride decreased significantly (p less than 0.01, P less than 0.001, and P less than 0.001, respectively). However, there were no significant changes in very-low-density-lipoprotein (VLDL) cholesterol and triglyceride or high-density-lipoprotein (HDL) cholesterol. Serum ubiquinone-10 levels did not change, and LDL levels of ubiquinone-10 decreased by 50 per cent, from 0.39 +/- 0.07 to 0.20 +/- 0.01 microgram per milliliter (P less than 0.05). No adverse effects were observed. We conclude that ML-236B is effective in lowering serum cholesterol without lowering serum ubiquinone-10 in heterozygous patients with familial hypercholesterolemia.

Topics: Adult; Aged; Cholesterol; Female; Heterozygote; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Lovastatin; Male; Middle Aged; Naphthalenes; Triglycerides; Ubiquinone

Topics: Acetates; Cell Line; Culture Media; Fibroblasts; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, LDL; Lovastatin; Naphthalenes; Ubiquinone

Compactin, a potent inhibitor of polyisoprenoid biosynthesis, induces abnormal gastrulation during sea urchin development at concentrations that have no effect on earlier embryonic development or on macromolecular synthesis. Three lines of evidence suggest that the developmental lesion caused by compactin results from inhibition of dolichol biosynthesis and a concomitant inhibition in the biosynthesis of the oligosaccharide chains of N-linked glycoproteins. (i) Embryos cultured in the presence of compactin gastrulate normally when supplemented with dolichol alone, whereas supplementation with cholesterol or coenzyme Q or both does not prevent the compactin-induced developmental lesion. (ii) Exogenously supplemented [3H]dolichol is incorporated into a compound with the chromatographic properties of oligosaccharide-pyrophosphoryldolichol. (iii) Embryos cultured in the presence of compactin exhibit a decreased capacity to synthesize mannose-labeled glycolipids and N-linked glycoproteins. This decrease in synthesis is abolished if the embryos are cultured in the presence of dolichol along with compactin.

Topics: Animals; Anti-Bacterial Agents; Cholesterol; Diterpenes; Dolichols; Gastrula; Glycoproteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Mannose; Morphogenesis; Naphthalenes; Sea Urchins; Ubiquinone