ubiquinone and lathosterol

HMG-CoA reductase inhibitors ('statins') have been associated with a decrease in ubidecarenone (ubiquinone) levels, a lipophilic enzyme also known as coenzyme Q10 (CoQ10), due to inhibition of mevalonate synthesis. There is speculation that a decrease in CoQ10 levels may be associated with statin-induced myopathy. The cholesterol absorption inhibitor ezetimibe increases endogenous cholesterol synthesis. The purpose of this study was to examine (i) the effects of ezetimibe and simvastatin on plasma CoQ10 levels and (ii) whether ezetimibe coadministered with simvastatin abrogates the suggested statin-induced decrease in the CoQ10 plasma levels.. Seventy-two healthy male subjects were enrolled in a single-centre, randomised, parallel-group study with three arms. Subjects received ezetimibe 10 mg/day, simvastatin 40 mg/day or the combination of ezetimibe 10 mg/day plus simvastatin 40 mg/day for 14 days.. Baseline CoQ10 (0.99 +/- 0.30 mg/L) levels for the combined groups remained unchanged in the ezetimibe group (0.95 +/- 0.24 mg/L), and significantly decreased in the simvastatin and combination groups (0.82 +/- 0.18 mg/L, p = 0.0002 and 0.7 +/- 0.22 mg/L, p < 0.0001, respectively). There was a correlation between the percentage change in the levels of low-density lipoprotein-cholesterol (LDL-C) and the percentage change in CoQ10 levels in all treatment groups (correlation coefficient [R] = 0.67, p < 0.0001). The ratios of CoQ10 levels to LDL-C levels were significantly increased in all treatment groups (p < 0.0001). CoQ10 level was independent of cholesterol synthesis or absorption markers.. Simvastatin and the combination of simvastatin and ezetimibe significantly decrease plasma CoQ10 levels whereas ezetimibe monotherapy does not. There is a significant correlation between the CoQ10 level decrease and the decrease in total and LDL-C levels in all three treatment groups, suggesting that the CoQ10 decrease may reflect the decrease in the levels of its lipoprotein carriers and might not be statin-specific. The statin-associated CoQ10 reduction is not abrogated through ezetimibe coadministration. Changes of CoQ10 levels are independent of cholesterol synthesis and absorption.

Topics: Adult; Anticholesteremic Agents; Azetidines; Cholestanol; Cholesterol; Cholesterol, LDL; Coenzymes; Drug Combinations; Ezetimibe, Simvastatin Drug Combination; Humans; Lipid Metabolism; Logistic Models; Male; Middle Aged; Reference Values; Simvastatin; Ubiquinone

Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle.. Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up.. The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 +/- 7.1 nmol/g to 41.2 +/- 27.0 nmol/g in the simvastatin group and from 22.6 +/- 8.6 nmol/g to 40.0 +/- 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 +/- 13.6 nmol/g to 26.4 +/- 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin.. High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.

Topics: Adult; Age Factors; Aged; Atorvastatin; Biopsy; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Citrate (si)-Synthase; Dose-Response Relationship, Drug; Double-Blind Method; Electron Transport; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Muscles; Patient Selection; Phytosterols; Pyrroles; Sex Factors; Simvastatin; Sitosterols; Succinate Cytochrome c Oxidoreductase; Time Factors; Ubiquinone

Plant stanols lower intestinal cholesterol absorption. This causes a decrease in serum low-density lipoprotein (LDL)-cholesterol, despite a compensatory increase in cholesterol synthesis. We therefore hypothesized that plant stanols also change LDL-cholesterol-standardized concentrations of ubiquinol-10 (a side product of the cholesterol synthesis cascade) and of those fat-soluble antioxidants that are mainly carried by LDL. To examine this, 112 nonhypercholesterolemic subjects consumed low erucic acid rapeseed oil (LEAR)-based margarine and shortening for 4 weeks. For the next 8 weeks, 42 subjects consumed the same products, while the other subjects received products with vegetable oil-based stanols (2.6 g sitostanol plus 1.2 g campestanol daily, n = 36) or wood-based stanols (3.7 g sitostanol plus 0.3 g campestanol daily, n = 34). Consumption of both plant stanol ester mixtures increased cholesterol synthesis and lowered cholesterol absorption, as indicated by increased serum cholesterol-standardized lathosterol and decreased plant sterol concentrations, respectively. Compared with the control group, absolute plasma ubiquinol-10 concentrations were lowered by 12.3% +/- 18.9% (-0.14 microg/mL v. the control group; P =.004; 95% confidence interval [CI] for the difference in changes, -0.05 to -0.22 microg/mL) in the vegetable oil-based group and by 15.4% +/- 13.0% (-0.17 microg/mL v. the control group; P <.001; 95% CI for the difference, -0.08 to -0.27 microg/mL) in the wood-based group. Changes in LDL-cholesterol-standardized ubiquinol-10 concentrations were not significantly changed. The most lipophylic antioxidants, the hydrocarbon carotenoids (beta-carotene, alpha-carotene, and lycopene), decreased most, followed by the less lipophylic oxygenated carotenoids (lutein/zeaxanthin and beta-cryptoxanthin) and the tocopherols. These reductions were related to the reduction in LDL, which carry most of these antioxidants. The decrease in the hydrocarbon carotenoids, however, was also significantly associated with a decrease in cholesterol absorption. LDL-cholesterol-standardized antioxidant concentrations were not changed, except for beta-carotene, which was still, although not significantly, lowered by about 10%. We conclude that the increase in endogenous cholesterol synthesis during plant stanol ester consumption does not result in increased LDL-cholesterol-standardized concentrations of ubiquinol-10, a side product of the cholesterol synthesis cascade. Fur

Topics: Absorption; Adolescent; Adult; Antioxidants; Carotenoids; Cholesterol; Cholesterol, LDL; Diet; Erucic Acids; Fats; Fatty Acids, Monounsaturated; Female; Humans; Male; Margarine; Middle Aged; Phytosterols; Plant Oils; Plants, Edible; Rapeseed Oil; Sitosterols; Solubility; Ubiquinone; Vitamin A; Vitamin E; Wood

Patients with heterozygous familial hypercholesterolemia (n = 12) were treated either with pravastatin, a specific inhibitor of HMG-CoA reductase, or cholestyramine, followed by a period of combined treatment with both drugs. Initially, these patients had increased serum levels of low density lipoprotein (LDL) cholesterol (8.77 +/- 0.48 mmol/l; SEM), lathosterol (5.32 +/- 0.60 mg/l), and ubiquinone (0.76 +/- 0.09 mg/l), while the serum dolichol concentration was in the normal range. Cholestyramine treatment (n = 6) decreased the levels of LDL cholesterol (-32%) and increased lathosterol (+125%), but did not change dolichol or ubiquinone levels in a significant manner. Pravastatin treatment (n = 6) decreased LDL cholesterol (-27%), lathosterol (-46%), and ubiquinone (-29%). In this case, the amount of dolichol in serum also showed a small but statistically insignificant decrease (-16%) after 12 weeks of treatment. Combined treatment with cholestyramine and pravastatin (n = 6) resulted in changes that were similar to, but less pronounced than, those observed during pravastatin treatment alone. In no case was the ratio between ubiquinone and LDL cholesterol reduced. Possible effects on hepatic cholesterol, ubiquinone, and dolichol concentrations were studied in untreated (n = 2), cholestyramine-treated (n = 2), and pravastatin-treated (n = 4) gallstone patients and no consistent changes could be observed. The results indicate that treatment with pravastatin in familial hypercholesterolemia decreases serum ubiquinone levels in proportion to the reduction in LDL cholesterol.

Topics: Adult; Aged; Cholesterol; Cholestyramine Resin; Dolichols; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Male; Mevalonic Acid; Middle Aged; Pravastatin; Ubiquinone