ubiquinone and Fatty-Liver

Mitochondrial redox imbalance and high Ca

Topics: Animals; Calcium; Diet, High-Fat; Fatty Liver; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; NADP Transhydrogenases; Permeability; Ubiquinone

As mitochondrial oxidative damage contributes to a wide range of human diseases, antioxidants designed to be accumulated by mitochondria in vivo have been developed. The most extensively studied of these mitochondria-targeted antioxidants is MitoQ, which contains the antioxidant quinone moiety covalently attached to a lipophilic triphenylphosphonium cation. MitoQ has now been used in a range of in vivo studies in rats and mice and in two phase II human trials. Here, we review what has been learned from these animal and human studies with MitoQ.

Topics: Administration, Oral; Animals; Antioxidants; Cations; Clinical Trials, Phase II as Topic; Disease Models, Animal; Fatty Liver; Humans; Liver Diseases; Mice; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Rats; Treatment Outcome; Ubiquinone

Mitochondria are the major sites of ATP synthesis through oxidative phosphorylation, a process that is weakened by proton leak. Uncoupling proteins are mitochondrial membrane proteins specialized in inducible proton conductance. They dissipate the proton electrochemical gradient established by the respiratory chain at the expense of reducing substrates. Several physiological roles have been suggested for uncoupling proteins, including roles in the control of the cellular energy balance and in preventive action against oxidative stress. This review focuses on new leads emerging from comparative proteomics about the involvement of uncoupling protein in the mitochondrial physiology. A brief overview on uncoupling proteins and on proteomics applied to mitochondria is also presented herein.

Topics: Animals; Carrier Proteins; Fatty Liver; Humans; Ion Channels; Membrane Proteins; Mitochondria; Mitochondria, Liver; Mitochondrial Proteins; Oxidation-Reduction; Proteomics; Purine Nucleotides; Recombinant Proteins; Ubiquinone; Uncoupling Agents; Uncoupling Protein 1

Previous work by ourselves and others showed that mitoquinone (mitoQ) reduced oxidative damage and prevented hepatic fat accumulation in mice made obese with high-fat (HF) feeding. Here we extended these studies to examine the effect of mitoQ on parameters affecting liver function in rats treated with HF to induce obesity and in rats treated with HF plus streptozotocin (STZ) to model a severe form of type 2 diabetes. In prior reported work, we found that mitoQ significantly improved glycemia based on glucose tolerance data in HF rats but not in the diabetic rats. Here we found only non-significant reductions in insulin and glucose measured in the fed state at sacrifice in the HF mice treated with mitoQ. Metabolomic data showed that mitoQ altered several hepatic metabolic pathways in HF-fed obese rats toward those observed in control normal chow-fed non-obese rats. However, mitoQ had little effect on pathways observed in the diabetic rats, wherein diabetes itself induced marked pathway aberrations. MitoQ did not alter respiration or membrane potential in isolated liver mitochondria. MitoQ reduced liver fat and liver hydroperoxide levels but did not improve liver function as marked by circulating levels of aspartate and alanine aminotransferase (ALT). In summary, our results for HF-fed rats are consistent with past findings in HF-fed mice indicating decreased liver lipid hydroperoxides (LPO) and improved glycemia. However, in contrast to the HF obese mice, mitoQ did not improve glycemia or reset perturbed metabolic pathways in the diabetic rats.

Topics: Animals; Blood Glucose; Cell Respiration; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Liver; Insulin; Lipid Metabolism; Liver; Male; Membrane Potential, Mitochondrial; Metabolomics; Mitochondria, Liver; Obesity; Organophosphorus Compounds; Oxidative Stress; Rats, Sprague-Dawley; Ubiquinone

Excess dietary sugar is associated with deleterious metabolic effects, liver injury, and coenzyme-Q10 (CoQ10) deficiency. This study investigates the ability of CoQ10 to protect against fructose-induced hepatic damage.. Rats were fed tap water or 30% fructose for 12 weeks with or without CoQ10 (10 mg/kg, po). An additional group of rats were allowed to feed on either water or 30% fructose for 12 weeks, followed by four weeks of treatment with either the vehicle or CoQ10.. Fructose-fed rats showed lower CoQ10 levels, increased systolic pressure, increased body weight, higher liquid consumption, decreased food intake and hyperglycemia. Fructose-fed rats also showed deteriorated serum and liver lipid profiles, impaired liver function tests and oxidative status, and lower expression of adiponectin receptor 1 and 2 along with higher GLUT-2 levels. Furthermore, following fructose treatment, tyrosine kinase-PI3K pathway was inhibited. Additionally, there was an increase in the levels of apoptotic markers and serum visfatin and a decrease in the levels of adiponectin and soluble receptor of the advanced glycated end product. Consequently, several histopathological changes were detected in the liver. Concurrent or three months post-exposure administration of CoQ10 in fructose rats significantly reversed or attenuated all the measured parameters and hepato-cytoarchitecture alterations.. This study suggests CoQ10 supplement as a possible prophylaxis or treatment candidate for fructose-induced liver injury.

Topics: Animals; Fatty Liver; Fructose; Liver; Male; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Ubiquinone

Maternal smoking leads to glucose and lipid metabolic disorders and hepatic damage in the offspring, potentially due to mitochondrial oxidative stress. Mitoquinone mesylate (MitoQ) is a mitochondrial targeted antioxidant with high bioavailability. This study aimed to examine the impact of maternal cigarette smoke exposure (SE) on offspring's metabolic profile and hepatic damage, and whether maternal MitoQ supplementation during gestation can affect these changes. Female Balb/c mice (eight weeks) were either exposed to air or SE for six weeks prior to mating and throughout gestation and lactation. A subset of the SE dams were supplied with MitoQ in the drinking water (500 µmol/L) during gestation and lactation. Intraperitoneal glucose tolerance test was performed in the male offspring at 12 weeks and the livers and plasma were collected at 13 weeks. Maternal SE induced glucose intolerance, hepatic steatosis, mitochondrial oxidative stress and related damage in the adult offspring. Maternal MitoQ supplementation reduced hepatic mitochondrial oxidative stress and improved markers of mitophagy and mitochondrial biogenesis. This may restore hepatic mitochondrial health and was associated with an amelioration of glucose intolerance, hepatic steatosis and pathological changes induced by maternal SE. MitoQ supplementation may potentially prevent metabolic dysfunction and hepatic pathology induced by intrauterine SE.

Topics: Animals; Antioxidants; Fatty Liver; Female; Lactation; Lipidomics; Male; Maternal Exposure; Metabolic Syndrome; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Organophosphorus Compounds; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Tobacco Smoke Pollution; Ubiquinone

Chronic alcohol-induced liver disease results in inflammation, steatosis, and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone (MitoQ) (5 and 25 mg/kg/day for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α), and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis, and induction of cytochrome P450 2E1 (CYP2E1). MitoQ had a minor effect on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities; however, it did decrease hepatic steatosis in ethanol-consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocked the increase in HIF1α in all ethanol-fed groups, which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis.. These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol-associated mitochondrial reactive oxygen species (ROS) and several downstream effects of ROS/RNS (reactive nitrogen species) production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependent HIF1α stabilization.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Cytochrome P-450 CYP2E1; Disease Models, Animal; Dose-Response Relationship, Drug; Electron Transport; Ethanol; Fatty Liver; Hypoxia-Inducible Factor 1, alpha Subunit; Lipid Metabolism; Liver; Male; Mitochondria, Liver; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Ubiquinone

Diets high in saturated fat and fructose have been implicated in the development of obesity and nonalcoholic steatohepatitis (NASH) in humans. We hypothesized that mice exposed to a similar diet would develop NASH with fibrosis associated with increased hepatic oxidative stress that would be further reflected by increased plasma levels of the respiratory chain component, oxidized coenzyme Q9 ((ox)CoQ9). Adult male C57Bl/6 mice were randomly assigned to chow, high-fat (HF), or high-fat high-carbohydrate (HFHC) diets for 16 weeks. The chow and HF mice had free access to pure water, whereas the HFHC group received water with 55% fructose and 45% sucrose (wt/vol). The HFHC and HF groups had increased body weight, body fat mass, fasting glucose, and were insulin-resistant compared with chow mice. HF and HFHC consumed similar calories. Hepatic triglyceride content, plasma alanine aminotransferase, and liver weight were significantly increased in HF and HFHC mice compared with chow mice. Plasma cholesterol (P < 0.001), histological hepatic fibrosis, liver hydroxyproline content (P = 0.006), collagen 1 messenger RNA (P = 0.003), CD11b-F4/80+Gr1+ monocytes (P < 0.0001), transforming growth factor beta1 mRNA (P = 0.04), and alpha-smooth muscle actin messenger RNA (P = 0.001) levels were significantly increased in HFHC mice. Hepatic oxidative stress, as indicated by liver superoxide expression (P = 0.002), 4-hydroxynonenal, and plasma (ox)CoQ9 (P < 0.001) levels, was highest in HFHC mice.. These findings demonstrate that nongenetically modified mice maintained on an HFHC diet in addition to developing obesity have increased hepatic ROS and a NASH-like phenotype with significant fibrosis. Plasma (ox)CoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing increased ROS associated with CD11b+F4/80+Gr1+ hepatic macrophage aggregation, resulting in transforming growth factor beta1-signaled collagen deposition and histologically visible hepatic fibrosis.

Topics: Animals; Body Composition; Collagen; Dietary Carbohydrates; Dietary Fats; Disease Models, Animal; Fatty Liver; Fructose; Insulin Resistance; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Obesity; Reactive Oxygen Species; Trans Fatty Acids; Transforming Growth Factor beta; Ubiquinone

The overproduction of very-low-density lipoprotein (VLDL) is a characteristic feature of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to use a high-fat diet-induced model of NAFLD in rats to investigate 1) the influence of the disease on hepatic VLDL processing in the endoplasmic reticulum and 2) the potential modulatory effects of dietary coenzyme Q (CoQ). Rats were fed a standard low-fat diet (control) or a diet containing 35% fat (57% metabolizable energy). After 10 wk, high-fat diet-fed animals were divided into three groups: the first group was given CoQ9 (30 mg*kg body wt(-1)*day(-1) in 0.3 ml olive oil), the second group was given olive oil (0.3 ml/day) only, and the third group received no supplements. Feeding (3 high-fat diets and the control diet) was then continued for 8 wk. In all high-fat diet-fed groups, the content of triacylglycerol (TG) and cholesterol in plasma VLDL, the liver, and liver microsomes was increased, hepatic levels of apolipoprotein B48 were raised, and the activities of microsomal TG transfer protein and acyl CoA:cholesterol acyltransferase were reduced. These findings provide new evidence indicating that VLDL assembly and the inherent TG transfer to the endoplasmic reticulum are altered in NAFLD and suggest a possible explanation for both the overproduction of VLDL associated with the condition and the disease etiology itself. Dietary CoQ caused significant increases in apolipoprotein B mRNA and microsomal TG levels and altered the phospholipid content of microsomal membranes. These changes, however, may not be beneficial as they may lead to the secretion of larger, more atherogenic VLDL.

Topics: Animals; Antioxidants; Apolipoproteins B; Diet; Fatty Liver; Lipid Metabolism; Lipoproteins, VLDL; Liver; Male; Microsomes, Liver; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ubiquinone

The aim of the present study was to examine the systemic parameters of oxidative stress and antioxidants in patients with nonalcoholic fatty liver disease and investigate the relationship between these parameters and clinical and biochemical outcomes.. Fifty-one male patients with nonalcoholic fatty liver disease (group I), 30 age-matched and body mass index (BMI)-matched healthy male subjects, and 30 age-matched male patients with chronic viral hepatitis (group II) were enrolled in the study.. Increased systemic levels of malondialdehyde and depletion of antioxidants such as coenzyme Q10, CuZn-superoxide dismutase, and catalase activity were observed in group I. Coenzyme Q10 and CuZn-superoxide dismutase correlated negatively with increasing necroinflammatory activity and fibrosis. Body fat was negatively associated with plasma coenzyme Q10 levels, while an inverse association was found between plasma catalase levels and TG. However, LDL was positively associated with plasma malondialdehyde levels. CuZn-superoxide dismutase levels were negatively associated with glucose, insulin, and HOMA-IR. In addition, the levels of CuZn-superoxide dismutase correlated significantly in a negative manner with BMI.. Our results concerning correlations suggest that disturbances in BMI, body fat, and lipid metabolism may contribute to altered oxidative status in NAFLD, and insulin resistance may be related to decreased antioxidants in NAFLD as well as products of lipid peroxidation. However, although our results suggest interesting correlations, this different mostly "weak" relationships must be taken with caution.

Topics: Adult; Antioxidants; Biomarkers; Body Composition; Body Mass Index; Catalase; Coenzymes; Complement C3a; Fatty Liver; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Insulin Resistance; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Reference Values; Statistics as Topic; Superoxide Dismutase; Ubiquinone

Hepatoprotective actions of metadoxina and ubiquinone have been studied in alcoholic rats by evaluating hepatic triglyceride accumulation and serum biochemical parameters of liver function. The two drug-treated groups displayed significantly lower triglyceride concentrations as compared to the ethanol-treated group. No significant differences were found among the two drug-treated and the control groups. Electron-microscopic abnormalities were found only in ethanol-treated rats. Serum biochemical parameters of liver function did not show any significant difference among all four groups. These results suggest a possible protective role of metadoxina and ubiquinone in ethanol-induced liver triglyceride accumulation.

Topics: Animals; Drug Combinations; Ethanol; Fatty Liver; Liver; Male; Osmolar Concentration; Pyridoxine; Pyrrolidonecarboxylic Acid; Rats; Time Factors; Triglycerides; Ubiquinone

Topics: Animals; Fatty Liver; Male; Mitochondria, Liver; Rats; Ubiquinone

Administration of an acutely intoxicating dose of ethanol produced significant increases in the concentration of liver triglyceride and enhanced the peroxidation of liver lipids in rats. Adipose triglyceride and lipid peroxide concentrations were unaltered. Coenzyme Q(4), an effective antioxidant, significantly inhibited accumulation of liver triglyceride following ethanol intoxication and prevented the peroxidation of liver lipids. These results, which demonstrate the selective ability of ethanol to induce peroxidation of liver lipids, together with the effectiveness of antioxidants, support the previously proposed hypothesis that peroxidation of liver lipids following ethanol intoxication is a factor in the pathogenesis of ethanol-induced liver injury.

Topics: Alcoholic Intoxication; Animals; Antioxidants; Fatty Liver; Female; Glycerides; Humans; In Vitro Techniques; Lipid Metabolism; Male; Peroxides; Rats; Triglycerides; Ubiquinone

Topics: Carbon Tetrachloride Poisoning; Electron Transport Complex II; Fatty Liver; Mitochondria; Seasons; Succinate Dehydrogenase; Ubiquinone