Open Access

Mitochondrial dysfunction in obesity: potential benefit and mechanism of Co-enzyme Q10 supplementation in metabolic syndrome

Journal of Diabetes & Metabolic Disorders201413:60

DOI: 10.1186/2251-6581-13-60

Received: 18 January 2014

Accepted: 3 May 2014

Published: 23 May 2014

Abstract

Co-enzyme Q10 (Co-Q10) is an essential component of the mitochondrial electron transport chain. Most cells are sensitive to co-enzyme Q10 (Co-Q10) deficiency. This deficiency has been implicated in several clinical disorders such as heart failure, hypertension, Parkinson’s disease and obesity. The lipid lowering drug statin inhibits conversion of HMG-CoA to mevalonate and lowers plasma Co-Q10 concentrations. However, supplementation with Co-Q10 improves the pathophysiological condition of statin therapy. Recent evidence suggests that Co-Q10 supplementation may be useful for the treatment of obesity, oxidative stress and the inflammatory process in metabolic syndrome. The anti-inflammatory response and lipid metabolizing effect of Co-Q10 is probably mediated by transcriptional regulation of inflammation and lipid metabolism. This paper reviews the evidence showing beneficial role of Co-Q10 supplementation and its potential mechanism of action on contributing factors of metabolic and cardiovascular complications.

Keywords

Metabolic syndrome Co-enzyme Q10 Obesity Inflammation Oxidative stress

Introduction

Metabolic syndrome is a cluster of disease symptoms such as dyslipidemia, hyperglycemia and insulin resistance, hypertension and visceral obesity [1]. Oxidative stress and inflammation are pivotal in all stages of atherosclerosis, hypertension, and non-alcoholic fatty liver and in subjects with metabolic syndrome [2, 3]. Mitochondrial dysfunction plays a crucial role in the development of diabetes and metabolic disorder [4]. Both, animal and clinical studies revealed that the sources of free radicals would be from mitochondrial origin [4]. The mitochondrial electron transport chain is the generator of free radicals mainly singlet oxygen (O.-) while producing the ATP from the substrate molecule. Free radicals may react with other important molecules within cells and enhance lipid peroxidation, oxidize proteins and damage DNA and are thus responsible for oxidative stress [2]. Inflammatory responses are also responsible for most of the organ dysfunction in metabolic disorder. Increased concentration and expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) are evident in adipocyte dysfunction and insulin resistance in obesity and metabolic syndrome [5]. Furthermore, inflammatory cells infiltration are also increased in adipose tissues which is responsible for adipocyte dysfunction [6]. Inflammation in adipose tissues could be a causative factor diminishing mitochondrial biogenesis and energy homoeostasis [79]. Therefore, supplementation with a dietary antioxidant having anti-inflammatory properties would be beneficial which can scavenge free radicals and restores antioxidant defence as well as suppresses inflammatory responses. Co-enzyme Q10 (Co-Q10), an integral part of the mitochondrial electron transport chain which transports electrons and acts as a natural antioxidant (Figure 1). Co-Q10 can also be found in much of the human diet. Beneficial effects of Co-Q10 supplementation have been noted for most of the symptoms of metabolic syndrome, e.g. hypertension, diabetes, liver diseases, insulin resistance and obesity. This review will thus, focus on the effect of Co-Q10 on various component of metabolic syndrome and elucidate its potential mechanism of action.
Figure 1

Schematic diagram of Co-Q10, Mito-Q and Idebenone.

Origin, chemistry and absorption of Co-Q10

Chemically Co-Q10 is a quinone molecule found almost in all cells of the body, hence the term ubiquinones [10]. It exists in nature and in the body, ubiquinones, the oxidized form and ubiquinol, the reduced form. Co-Q10 serves as an essential carrier for the electron transfer in the mitochondrial respiratory chain for the synthesis of ATP. Co-Q10 was first isolated in 1957 from beef mitochondria [10]. Folkers et al. revealed the chemical structure of Co-Q10 in 1958 [11]. Meat, poultry and fish are the richest sources of Co-Q10, and the daily intake of these foods provides between 3 to 5 mg of Co-Q10 [12, 13]. The absorption of Co-Q10 from the diet occurs mainly in the small intestine and is better absorbed in presence of lipid rich foods [14]. Co-Q10 is then transported to the liver and form lipoprotein complex and deposited in tissues [14]. Tissues with high-energy requirements and metabolic rates such as the heart and the skeletal muscle contain relatively high concentrations of Co-Q10 [15]. About 95% of Co-Q10 in human circulatory system exists in its reduced form as ubiquinol [16]. The safety of high doses of orally-ingested Co-Q10 over long periods is well documented in human [17] and also in animals [18]. Co-Q10 dosages generally range from 100 to 200 mg a day for patients suffering cardiovascular disease [19].

Mitochondrial biogenesis and Co-Q10

Mitochondrial biogenesis means the increased number and function of mitochondria due to the response of increased cellular energy demand and thereby increased ATP production. Generally, mitochondrial electron transport chain consists of several protein complexes, namely, complex I, complex II, complex III and complex IV etc. [20]. NADH which donates electrons to complex I and FADH2 feed the electron to complex II. Glucose oxidation through glycolysis and pyruvate dehydrogenase to acetyl CoA generates NADH. In contrast, fatty acid oxidation to acetyl-CoA generates FADH2 through the process of β-oxidation. Acetyl CoA from both sources feeds the TCA cycle. Electrons coming from NADH and FADH2 are thus transported via reduced Co-Q10 to Complex III [20]. The proton gradient is generated as a consequence of this sequential process, drives complex V or the ATPase to produce ATP. ATP is thus transported via ANP to its target site. In presence of uncoupling agent, the protomotive force will divert to UCPs and a proton leak occurs. Thus the energy will expend as heat without producing any ATP. Complex I and complex III are the primary sources of O2 free radicals due to incomplete reduction of the oxygen molecule. The Mitochondrial environment maintains a highly protective defence against this free radical. In normal physiological conditions these free radicals are scavenged by superoxide dismutase of mitochondrial origin and later by catalase in cytosol. Diabetic hyperglycemia and metabolic disorder are responsible for the inactivity of these antioxidant enzyme systems and decreased mitochondrial function. Several evidences suggest that, inhibition of the mitochondrial electron transport chain activity may increase lipid accumulation in adipocyte [21, 22].

Mitochondrial biogenesis can be modulated by several transcriptional regulators present in the cell. Peroxisome proliferator activated receptor (PPAR) family is such a regulator of mitochondrial biogenesis [23]. Three types of PPAR proteins have been identified so far, PPAR-α, PPAR-γ and PPAR-δ [24]. PPARs activation is also important for lipid metabolism, adipocyte differentiation and the prevention of inflammation [24]. Moreover, PPARs also regulate mitochondrial biogenesis via an activator called peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) [25, 26]. PGC-1α is physiologically regulated by exercise [27, 28] and calorie restriction [29]. Apart from these exercise and calorie restriction means, pharmacological agents such as fenofibrates [30] and resveratrol [31] stimulate PGC-1α and restore mitochondrial function. Co-Q10 mediated activation of PPARs are revealed only recently which would be a possible mechanism of energy homeostasis in failing tissues and obesity [32].

Metabolic disorder due to Co-Q10 deficiency

Ogashara et al. described the first patients (two sisters) with primary Co-Q10 deficiency in 1989 [33]. They had progressive muscle weakness, abnormal fatigue, and central nervous system dysfunction from early childhood characterized by a low Co-Q10 concentration in their muscles. Both patients improved remarkably with oral Co-Q10 [33]. Maintaining adequate Co-Q10 level throughout the body is important for normal function and health. Plasma concentrations of Co-Q10 are high in healthy infant and children and declining with age [34, 35]. Metabolic disorder may arise due to Co-Q10 deficiency. Growing bodies of evidences indicate that oxidative stress plays a critical role in the pathogenesis of type 2 diabetes mellitus and its complications [36]. Low plasma Co-Q10 concentrations were found in patients with poor glycaemic control and diabetic complications [3740].

HMG-CoA reductase inhibitors (statins) reduce Co-Q10 levels in human [41, 42]. Alternatively, supplementation with oral Co-Q10 can restore plasma Co-Q10 levels in patients receiving statin therapy [4143]. Statin mediated Co-Q10 depletion affects muscle function. Patients taking statin to reduce plasma lipids suffered myalgia and myopathic pain [4446]. Myocardial depletion of Co-Q10 has also been demonstrated in heart failure patients with cardiomyopathy which was improved by Co-Q10 therapy [47]. An important factor contributing to statin related myopathy may be a genetic susceptibility to muscle disorders and underlying metabolic mechanisms [48, 49]. Due to the statin therapy, genomic variation has been found in COQ2 gene which encoding para-hydroxybenzoate-polyprenyl transferase for CoQ10 biosynthesis [48]. Another report suggests that statins may affect energy metabolism (Carnitine palmitoyltransferase II deficiency) combined with a genetic susceptibility triggering myopathic outcomes in certain high-risk patients [49].

Antioxidant effect of Co-Q10

Benzoquinone group of Co-Q10 is able to accept and donate electrons which is a critical feature for an antioxidant [14]. It scavenges free radicals and inhibits lipid and protein peroxidation. Vitamin E and Co-Q10 prevents lipid peroxidation at nearly the same rate [50]. However, Co-Q10 prevents LDL oxidation more efficiently than α-tocopherol, lycopene, or β-carotene [51]. Co-Q10 also enhances the availability of other antioxidants such as vitamin C, vitamin E and beta-carotene [52]. Direct elimination of free radical such as lipid peroxyl, peroxyl and/or alkoxyl radicals in vitro and in vivo as a consequence of Co-Q10 supplementation was reported by several investigators [53, 54]. Co-Q10 may also serve as an antioxidant by acting as a cofactor and activator of mitochondrial uncoupling proteins, leading to a reduction in free radical generation in vivo[55]. H2O2-induced DNA strand breaks in lymphocytes are protected by ubiquinol-10 [56]. In another study, in vivo supplementation with Co-Q10 was shown to enhance the recovery of human lymphocytes from oxidative DNA damage [57]. Improved cellular antioxidant enzyme activity was also noted for Co-Q10 supplementation. Co-Q10 treatment increased antioxidant enzyme activity of superoxide dismutase, catalase, and glutathione in the liver homogenates of diabetic rats followed by reduced lipid peroxidation [58]. Antioxidant enzyme, catalase activity and GSH concentration were also improved in liver of acetaminophen induced rats [59]. A recent clinical study also showed that Co-Q10 supplementation at a dose of 150 mg decreased oxidative stress and improved antioxidant enzyme activity in patients with coronary artery disease [60].

Effect of Co-Q10 on inflammation and metabolic syndrome

Inflammation is a response to tissue or organ damage from exogenous and endogenous factors and assists in the restoration of impaired homeostasis. Several inflammatory cytokine are also generated e.g. interleukin-1 (IL-1), interleukin-6 (IL 6), tumour necrosis factor- α (TNF-α) etc. which have both systemic and local effect. Local effects are associated with increased expression of adhesion cell molecules such as intracellular adhesion molecule-1 (ICAM-1), selectins and heat-shock proteins [61]. Macrophage infiltration and fibroblast activation are two inflammatory responses develop chronically in inflamed adipose tissues [6, 62]. Systemic chronic inflammatory response is also considered to be a mediator of metabolic syndrome and insulin resistance [62, 63]. Pro-inflammatory cytokines and oxidative stress have been shown to be responsible for developing metabolic disturbances, such as insulin resistance and activation of immune response in liver, adipose tissue and in muscle [6466]. Moreover, activation of inflammatory pathways in hepatocytes is sufficient to cause both local as well as systemic insulin resistance [67, 68]. Recent studies have confirmed positive association between obesity indices and inflammatory markers, mainly c-reactive protein (CRP) and other inflammatory cytokines [6971]. Evidence is also starting to accumulate that inflammatory cytokines are over expressed in adipose tissues of obese rodent models and obese humans [7275]. Some other studies suggest that systemic administration of the TNF-α also induces insulin resistance in experimental animal [76, 77]. In recent years, several inflammatory signal mechanisms have been described such as c-JUN kinase (JNK) pathways, protein kinase-C (PKC) and IκB kinase (IKK) mediated nuclear factor- κB (NF-κB) pathways and suppressor of cytokine signaling (SOCS) family mediated pathways [63]. Furthermore, PKC and IKK can be activated by increased fatty acid level in cells [63].

Low density lipoprotein (LDL) cholesterol oxidation is the key regulator for developing inflammation in endothelial cells and other tissues [78]. The LDL receptor plays a vital role in increasing uptake of cholesterol from plasma to cell and increasing clearance of apoB and apoE-containing lipoproteins [79]. In diabetes and obesity, LDL-R populations decrease and increase LDL level in plasma [80]. LDLR-/- mice showed an increased plasma lipid profile and an increase in inflammatory markers in response to high fat diet [79, 81, 82]. The anti-atherogenic effect of PPARγ agonist was seen in LDLR-/- male mice which is correlated with improved insulin sensitivity and decreased tissue expression of TNF-α and gelatinase B [83]. However, peroxisome proliferator activated receptor-γ (PPAR-γ) is reported to attenuate inflammation in activated macrophages by interfering with NF-κB signalling [84]. PPAR-α is another analogue of the PPAR family also regulates anti-inflammatory genes (Figure 2) [85].
Figure 2

Proposed mechanism of Co-Q supplementation on anti-inflammatory and lipid metabolism pathways in tissues in case of metabolic syndrome. AMPK, Adenosine monophosphate activated protein kinase; PPAR, Peroxisome proliferator activated receptor; PGC-1α, Peroxisome proliferator-activated receptor gamma coactivator-1; oxLDL, Oxidized Low density lipoprotein; NRF, nuclear respiration factor; LXR, Liver X receptor; PPRE PPAR response element.

The anti-inflammatory activity of Co-Q10 is well documented. Stimulation of cells with LPS resulted in a distinct release of TNF-α, macrophage inflammatory protein-1 alpha (MIP-1α) and monocyte chemo attractant protein-1 (MCP-1) which were significantly attenuated by pre-incubation of cells with the reduced form of Co-Q10 [86, 87]. Treatment with CoQ10 also reduced the elevated plasma lipid profiles and decreased mRNA expression of the pro-inflammatory cytokine TNF-α in adipose tissues of ob/ob mice [88]. CoQ10 supplementation also improved the inflammatory state in liver of high fat fructose diet fed rats [89]. Recent evidence suggests that Co-Q10 can serve as an agonist of PPARs and activates the PPAR mediated anti-inflammatory response (Figure 2) [90, 91].

Effect of Co-Q10 on endothelial dysfunction and hypertension

Endothelial dysfunction and hypertension are common in metabolic syndrome. Increased glucose intolerance and oxidative stress plays a critical role in the development of endothelial dysfunction in aortas of diabetic rats [36]. Co-Q10 supplementation improved the endothelial dysfunction in the mesenteric arteries in high fat diet fed SHRsp rats [92]. Inflammatory cell infiltration may be a potential mediator of inflammation and endothelial dysfunction in aortas. Co-Q10 prevented the lymphocytic infiltration in perivascular area of aortas from fructose fed rats [93]. Co-Q10 also improved endothelial dysfunction in statin-treated type II diabetic patients [94]. Considerable evidence indicates that oxLDL-induced endothelial dysfunction is associated with down-regulation of eNOS and up-regulation of inducible nitric oxide synthase (iNOS). A recent study showed that Co-Q10 prevented apoptosis in human umbilical vein endothelial cells (HUVEC) due to oxLDL by preventing the NF-kB mediated caspase-3 activation [95]. Co-Q10 also attenuated the oxLDL-mediated down-regulation of endothelial nitric oxide synthase (eNOS) and up-regulation of inducible nitric oxide synthase (iNOS) [95]. oxLDL induced inflammatory process and expression of adhesion molecules, release of pro-inflammatory cytokines and the adherence of monocyte were also attenuated by CoQ10 in THP-1 cells [95]. Extracellular superoxide dismutase (ecSOD) activity and endothelium-dependent vasodilatation were also improved remarkably after CoQ10 supplementation which alters local vascular oxidative stress [96].

The antihypertensive effect of Co-Q10 is also well documented in animal and human studies. Co-Q10 supplementation reduced hypertension and cardiac hypertrophy in DOCA-salt hypertensive rats [97, 98]. The Co-Q10 analogue decylubiquinone (10 mg/kg) reduced the systolic blood pressure, plasma malondialdehyde, total cholesterol and LDL-cholesterol in the SHRsp rats [99]. A recent meta-analysis of clinical trials investigating the use of Co-Q10 for treatment of hypertension considered 12 trials since 1975 and found beneficial effect of Co-Q10 supplementation [100]. Among these trials, four were prospective randomized trials and eight trials considering the effect of Co-Q10 on final blood pressure compared with previous level [100]. Co-Q10 supplementation has shown to be effective in lowering blood pressure in diabetes, improves the glycaemia control in metabolic syndrome; however, a recent study showed that Co-Q10 treatment failed to reduce blood pressure in patients with uncontrolled hypertension [101]. Another study suggests that treatment with Co-Q10 (50 mg twice a day for ten weeks) in patients with essential hypertension reduced hypertension without affecting the plasma renin activity, serum and urinary sodium and potassium, and urinary aldosterone [102]. These results suggest that treatment with Co-Q10 decreases blood pressure in patients with essential hypertension, possibly because of a reduction in peripheral resistance [102]. However, the exact mechanism is not known, but one theory proposed that it reduces peripheral resistance by preserving nitric oxide bioavailability [103]. Alternatively, coenzyme Q10 may increase the synthesis and sensitivity of prostacyclin (PGI2), a potent vasodilator and inhibitor of platelet aggregation, to arterial smooth muscle and does relaxation to arteries [104].

Effect of Co-Q10 on cardiac dysfunction

Clinically, Co-Q10 has potential for the prevention and treatment of cardiovascular diseases such as myocardial infarction, congestive heart failure and other drug- induced/disease induced cardiomyopathies [105]. The heart is highly sensitive to Co-Q10 deficiency. Defective levels of specific oxidative phosphorylation/respiratory enzyme activities and reduced energy reserve in heart failure may be considered as contributing factors for the progression of disease [106]. Low levels of Co-Q10 concentration were found in 70–75% of patients with aortic stenosis or insufficiency, mitral stenosis or insufficiency, diabetic cardiomyopathy, atrial septal defects and ventricular septal defects [107]. Circulating levels of Co-Q10 were also significantly lower in patients with ischemic heart disease and in patients with dilated cardiomyopathy as compared to healthy controls [108]. Pepe et al. have reviewed the meta analysis of clinical trials of Co-Q10 in heart failure, reporting that cardiac output, cardiac index and stroke volumes were improved with the treatment of Co-Q10 [103]. Diastolic dysfunction is one of the earliest identifiable signs of myocardial failure due to severe thickening of the left ventricles, which accounts for 30-49% of heart failure cases. Patients treated with 200 mg/day of Co-Q10 improved interventricular septal thickness significantly with improved symptoms of fatigue and dyspnea with no side effects noted [109]. Studies on isolated rat’s heart also demonstrated a protective effect of Co-Q10 against ischemia and reperfusion injuries [110, 111]. Pre-treatment with Co-Q10 improved recovery of cardiac function, aerobic efficiency and enzyme levels in young healthy rats compared to untreated controls undergone experimentally induced ischemia-reperfusion in heart [112]. In an another study, mice pre-treated with Co-Q10 for 4 days prior to toxic doses of adriamycin, survival rates were significantly higher (80%) compared to the mice not received the supplements (40%) [113]. This Co-Q10 mediated protection against adriamycin induced cardiac toxicities is probably due to the inhibition of lipid peroxidation and induction antioxidant enzymes in cardiac tissue [114].

Effect of Co-Q10 on diabetes and insulin resistance

Coenzyme Q concentrations appear to be reduced in diabetic states. Diabetic animals showed decreased Co-Q10 concentration in heart, liver and skeletal muscle [115]. Evidence also exists for reduced Co-Q in plasma of humans with diabetes. Lower plasma levels of CoQH2 have been found in diabetic patients than healthy subjects [37, 116]. Supplementation with Co-Q10 would be beneficial for diabetes and insulin resistance. Co-Q10 supplementation (10 mg/kg) improved the elevated glucose concentration and glucose intolerance in STZ induced diabetic rats without affecting the insulin concentration [58]. However, 200 mg of Co-Q10 daily for 6 months did not improve glycemic control or serum lipid levels of Type-2 diabetics [117]. In another randomized double-blind, placebo-controlled study, Co-Q10 supplementation at a dose 100 mg for three months failed to improve HbA1c, mean daily blood glucose concentrations, mean insulin dose, number of hypoglycemic episodes or cholesterol concentrations compared to the placebo group [118]. Improved glycemic control due to Co-Q10 supplementation could be a protective action against pancreatic beta cell destruction in diabetes. Co-Q10 supplementation did not reduce the pancreatic damage, inflammation and beta cell loss in diabetic rats but decrease glycated HbA1c and pancreatic lipid peroxidation [119]. Further researches are required to evaluate the hypoglycaemic action of Co-Q10 supplementation.

Liver steatosis and effect of Co-Q10 on hepatic dysfunction

Oxidative stress and inflammatory responses are responsible for hepatic damage and fibrosis. The liver X receptors (LXR) constitute a class of nuclear receptors activated by oxidized lipids (Figure 2). Activation of LXR in macrophages induces expression of several genes involved in lipid metabolism and reverse cholesterol transport [120]. Activation of these transcription factors inhibits inflammatory gene expression in macrophages and adipocytes, largely through PPAR-γ mediated suppression of NF-κB signalling [121, 122]. LXR also plays an important role in lipid and cholesterol metabolism. LXRα knockout mice develop enlarged fatty livers, degeneration of liver cells, high cholesterol levels in liver, and impaired liver function when fed a high-cholesterol diet [123]. Generally, oxidized LDL serves as an agonist of LXR and modulates PPAR binding to DNA sequence elements termed peroxisome proliferator response elements (PPRE) [124]. Thus, antioxidants such as Co-Q10 may prevent LDL oxidation and serve as an LXR antagonist. Recent report showed that reduced form of Co-Q10 downregulated genes involved in cholesterol biosynthesis (HMGCS1, HMGCL and HMGCR) which are also deactivated by transcriptional regulators PPARα and LXR/RXR complex in liver of SAMP1 mice [125]. However, oxidized form of Co-Q10 did not alter the genes expression of HMGCS1, HMGCL and HMGCR [91, 125]. A recent report also suggests that LXRs influence CoQ synthesis without directly regulating the process and CO-Q10 concentration was found to be decreased in liver of LXR-α knockout mice and LXR double knockout mice [126].

A high fat diet and fructose feeding can also cause dyslipidemia and hepatic steatosis. Co-Q10 supplementation increases life-span of rats fed a diet enriched with polyunsaturated fatty acids [127, 128]. High fat diet induced hepatic oxidative stress in rats was improved by supplementation with Co-Q10 followed by the improvement of the plasma lipid profile [89]. The lipid lowering effect of Co-Q10 supplementation was also seen in fructose fed rats [93]. A Co-Q10 analogue, Q monomethyl ether, also showed beneficial effect on progressive non-alcoholic fatty liver (NAFL) in rats fed a high fat diet and improved liver architecture by preventing the fat droplet accumulation in hepatocytes [129]. Increased fatty acid beta oxidation would be the potential mechanism of improving lipid profile in metabolic syndrome. Scanty literature was found on any effect of Co-Q10 on mitochondrial fatty acid beta oxidation. However, up regulation of the beta oxidation gene was observed in animal treated with ubiquinol [90]. Recent evidence suggests that this up-regulation of fatty acid oxidation is probably involved PPAR mediated pathways [90]. It is now evident that ubiquinol, a reduced form of Co-Q10, may be an activator of PPAR gene expression and activated a series of lipid metabolizing gene family in mice [90, 91]. Alternatively, ubiquinol downregulated a series of genes involved in cholesterol and fatty acid synthesis such as HMGCS1, HMGCL and HMGCR [91]. These genes are also negatively regulated by PPAR mediated pathways.

Co-Q10 supplementation also showed hepatic protection in other model of hepatic dysfunction. Co-Q10 treatment showed hepatic protection against acetaminophen induced liver toxicities in rats [59]. Co-enzyme Q10 treatment improved extensive centrilobular necrosis, cytoplasmic vacuolization and ballooning degeneration of hepatocytes with congested sinusoids in liver of rats [59]. Hepatic protection in these rats depends on the blocking NF-kB mediated inflammatory signal pathways and inactivation of caspase activity [59]. Co-Q10 supplementation is also effective in preventing the toxin induced hepatic damage [130]. Co-Q10 supplementation in diet also showed hepatic protection in aged rats due to enhanced cellular antioxidant action [131].

Effect of Co-Q10 on obesity and fat metabolism

Generally, obese individuals showed a reduction of fat metabolism and increased fat deposition in the body. Increased fat deposition is responsible for the hyperglycemia, insulin resistance, dyslipidemia and hypertension, most of the common features of metabolic syndrome [132]. Mitochondrial dysfunction and reduced Co-Q10 concentration was found in obese individual [133]. Adipocyte differentiation and fat deposition into adipocytes play important roles in obesity. Co-Q10 prevents adipogenesis in rosiglitazone induced adipogenesis in ob/ob mice [88]. Anti-adipogenic activity of Co-Q10 was also shown in 3 T3-F442A cell line. Inhibition of Co-Q10 synthesis strongly triggered adipocyte differentiation while increment of Co-Q 10 synthesis strongly inhibited adipocyte differentiation [134]. Co-Q10 treatment increases fat oxidation and energy expenditure in inguinal white adipose tissue. Decreased mRNA expression of the lipogenic enzymes fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1), and the glycerogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) are responsible for the lipid lowering effect of Co-Q10 [88]. In this study, mRNA expression of proteins involved in mitochondrial biogenesis (peroxisome proliferator-activated receptor-g coactivator-1 (PGC-1)), oxidative phosphorylation system (OXPHOS) system (cytochrome oxidase subunit IV (COIV)), fatty acid transport into mitochondria (carnitine-palmitoyl transferase 1, muscle isoform (M-CPT1)) and energy expenditure (uncoupling protein-1 (UCP1)) were also increased to promote the fatty acid utilization in high fat diet fed mice [88]. AMPK regulates the expression of lipogenic genes, including fatty acid synthesis (FAS) [135]. Co-Q10 increased the AMPK phosphorylation in 3 T3-L1preadipocytes probably by increasing the cytoplasmic calcium concentrations followed by increased Ca2+/calmodulin-dependent protein kinase kinase (CaMKK). Moreover, Co-Q10 increased fatty acid oxidation in 3 T3-L1preadipocytes and increased PPARα in protein and mRNA level [32]. This AMPK-mediated PPARα induction at least in part causes suppression of adipocyte differentiation [32].

Future perspectives and conclusion

Co-Q10 has proven potential as an antioxidant molecule with anti-inflammatory properties. Recent evidence also suggests that Co-Q10 may serve as AMPK and PPARs activators and increases the fat burning capacity of cells (Table 1). Its use is still limited due to poor water solubility and lipophilic nature. Several analogues have so far been synthesized such as mito-Q and idebenone.
Table 1

Effect of Co-Q10 supplementation on lipid metabolism in metabolic syndrome

Parameter

Model and dose

Effect and potential mechanism

Reference

Lipid metabolism

3 T3-L1 pre-adipocytes

-Increases fatty acid beta oxidation.

[32]

- ↑ Ca++ Influx; ↑AMPK; ↑PPAR-α.

-Prevents adipocytes differentiation

Fructose fed rat

-↓Total cholesterol; ↓LDL-Cholesterol; ↓triglycerides

[93]

ob/ob mice

- ↓ Total cholesterol; ↓triglycerides; ↓NEFA

[88]

- ↓ mRNA expression of the lipogenic enzymes such as fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1).

C57BL6J mice

- Increases fatty acid beta oxidation

[90]

Mito-Q10 comprises a lipophilic triphenylphosphonium cation covalently attached to an ubiquinol antioxidant [136]. The lipophilic triphenylphosphonium cation helps this molecule to easily cross the lipid bilayer, be orally bio-available and accumulate in mitochondria several hundred fold compared with Co-Q10 itself [136]. MitoQ10 has been shown to be effective against mitochondrial oxidative damage in vivo and in rodent models of sepsis and reperfusion injury of heart [137, 138]. Administration of MitoQ10 also protects against the development of hypertension, improves endothelial function, and reduces cardiac hypertrophy in young stroke-prone spontaneously hypertensive rats [139]. MitoQ, was shown to completely prevent mitochondrial abnormalities as well as cardiac dysfunction characterized by a diastolic dysfunction [140]. Recent evidence suggests that Mito-Q is effective against ethanol induced micro and macro hepatic steatosis in rats [141]. Metabolic dysfunctions were also improved in mice treated with Mito-Q. Mito-Q supplementation reduced the fat mass and plasma lipid profile in ApoE-/- mice [142]. MitoQ supplementation also improved hyperglycemia, hepatic steatosis and decreased DNA oxidative damage (8-oxo-G) in multiple organs of ApoE-/- mice [142]. Idebenone, a benzoquinone carrying exactly the same quinone moiety as Co-Q0, Co-Q1 and Co-Q10, shows multiple activities in vitro and in vivo. Idebenone is quickly absorbed and is well tolerated and safe given as single or repeated daily doses [143]. Like Co-Q10, idebenone also prevents lipid peroxidation and ROS production in vivo[144146]. However, to date, no more literature has been found with an idebenone effect on diabetes and metabolic syndrome. In view of the above discussion, Co-Q10 supplementation has proven its efficacy and benefit to treat metabolic syndrome and obesity. Further research is warranted to get benefit in a clinical setup.

Abbreviations

AMPK: 

Adenosine monophosphate activated protein kinase

ATP: 

Adenosine triphosphate

CAT: 

Catalase

ERK: 

Extracellular receptor kinase

GPx: 

Glutathione peroxidase

GST: 

Glutathione S-transferase

HUVEC: 

Human umbilical vein endothelial cell

IL-6: 

Interleukin 6

IRS: 

Insulin receptor substrate

LDL: 

Low density lipoprotein

LXR: 

Liver X receptor

MAPK: 

Mitogen activated protein kinase

MCP-1: 

Monocyte chemotactic protein-1

mtTFA: 

Mitochondrial transcription factor A

NO: 

Nitric oxide

NRF: 

Nuclear respiration factor

PGC-1α: 

Peroxisome proliferator-activated receptor gamma coactivator-1α

PPAR: 

Peroxisome proliferator activated receptor

PPRE: 

PPAR response element

ROS: 

Reactive oxygen substrate

SOD: 

Superoxide dismutase

STZ: 

Streptozotocine

TNF: 

Tumour necrosis factor

VSMC: 

Vascular smooth muscle cell

oxLDL: 

Oxidized low density lipoprotein

VCAM-1: 

Vascular cell adhesion molecule-1

UCP-1: 

Uncoupling protein- 1.

Declarations

Acknowledgements

Md. Ashraful Alam was supported by Islamic Development Bank Merit PhD Scholarship and The University of Queensland Tuition Scholarship.

Authors’ Affiliations

(1)
School of Biomedical Science, The University of Queensland
(2)
Department of Pharmaceutical Sciences, North South University

References

  1. Huang PL: A comprehensive definition for metabolic syndrome. Dis Model Mech 2009, 2: 231–237. 10.1242/dmm.001180PubMedPubMed CentralGoogle Scholar
  2. Roberts CK, Sindhu KK: Oxidative stress and metabolic syndrome. Life Sci 2009, 84: 705–712. 10.1016/j.lfs.2009.02.026PubMedGoogle Scholar
  3. Hopps E, Noto D, Caimi G, Averna MR: A novel component of the metabolic syndrome: the oxidative stress. Nutr Metab Cardiovasc Dis 2010, 20: 72–77. 10.1016/j.numecd.2009.06.002PubMedGoogle Scholar
  4. Patti M-E, Corvera S: The role of mitochondria in the pathogenesis of type 2 diabetes. Endocrine Rev 2010, 31: 364–395. 10.1210/er.2009-0027Google Scholar
  5. Hotamisligil GS, Spiegelman BM: Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 1994, 43: 1271–1278.PubMedGoogle Scholar
  6. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003, 112: 1796–1808. 10.1172/JCI200319246PubMedPubMed CentralGoogle Scholar
  7. Savage DB, Petersen KF, Shulman GI: Mechanisms of insulin resistance in humans and possible links with inflammation. Hypertension 2005, 45: 828–833. 10.1161/01.HYP.0000163475.04421.e4PubMedGoogle Scholar
  8. Nisoli E, Clementi E, Carruba MO, Moncada S: Defective mitochondrial biogenesis. Circ Res 2007, 100: 795–806. 10.1161/01.RES.0000259591.97107.6cPubMedGoogle Scholar
  9. Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Palomba L, Cantoni O, Clementi E, Moncada S, Carruba MO, Nisoli E: TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J Clin Invest 2006, 116: 2791–2798. 10.1172/JCI28570.PubMedPubMed CentralGoogle Scholar
  10. Bonakdar RA, Guarneri E: Coenzyme Q10. Am Fam Physician 2005, 72: 1065–1070.PubMedGoogle Scholar
  11. Littarru GP, Tiano L: Clinical aspects of coenzyme Q-10; in relationship with its bioenergetic and antioxidant properties. In Mitochondrial Medicine. Edited by: Gvozdjakova A. Netherlands: Springer; 2008:303–321.Google Scholar
  12. Pravst I, Žmitek K, Žmitek J: Coenzyme Q10 contents in foods and fortification strategies. Crit Rev Food Sci Nutr 2010, 50: 269–280. 10.1080/10408390902773037PubMedGoogle Scholar
  13. Weber C, Bysted A, Hølmer G: Coenzyme Q10 in the diet-daily intake and relative bioavailability. Mol Aspects Med 1997, 18(Supplement 1):251–254.Google Scholar
  14. Greenberg S, Frishman WH: Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol 1990, 30: 596–608. 10.1002/j.1552-4604.1990.tb01862.xPubMedGoogle Scholar
  15. Bhagavan HN, Chopra RK: Coenzyme Q10: absorption, tissue uptake, metabolism and pharmacokinetics. Free Radic Res 2006, 40: 445–453. 10.1080/10715760600617843PubMedGoogle Scholar
  16. Aberg F, Appelkvist EL, Dallner G, Ernster L: Distribution and redox state of ubiquinones in rat and human tissues. Arch Biochem Biophys 1992, 295: 230–234. 10.1016/0003-9861(92)90511-TPubMedGoogle Scholar
  17. Langsjoen PH, Langsjoen PH, Folkers K: Long-term efficacy and safety of coenzyme Q10 therapy for idiopathic dilated cardiomyopathy. Am J Cardiol 1990, 65: 521–523. 10.1016/0002-9149(90)90824-KPubMedGoogle Scholar
  18. Williams KD, Maneke JD, AbdelHameed M, Hall RL, Palmer TE, Kitano M, Hidaka T: 52-Week oral gavage chronic toxicity study with ubiquinone in rats with a 4-week recovery. J Agric Food Chem 1999, 47: 3756–3763. 10.1021/jf981194tPubMedGoogle Scholar
  19. Langsjoen PH, Langsjoen AM: Coenzyme Q10 in cardiovascular disease with emphasis on heart failure and myocardial ischaemia. Asia Pacific Heart J 1998, 7: 160–168. 10.1016/S1328-0163(98)90022-7Google Scholar
  20. Dallner G, Sindelar PJ: Regulation of ubiquinone metabolism. Free Radic Biol Med 2000, 29: 285–294. 10.1016/S0891-5849(00)00307-5PubMedGoogle Scholar
  21. Vankoningsloo S, Piens M, Lecocq C, Gilson A, De Pauw A, Renard P, Demazy C, Houbion A, Raes M, Arnould T: Mitochondrial dysfunction induces triglyceride accumulation in 3 T3-L1 cells: role of fatty acid beta-oxidation and glucose. J Lipid Res 2005, 46: 1133–1149. 10.1194/jlr.M400464-JLR200PubMedGoogle Scholar
  22. Choo HJ, Kim JH, Kwon OB, Lee C, Mun J, Han S, Yoon YS, Yoon G, Choi KM, Ko YG: Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 2006, 49: 784–791. 10.1007/s00125-006-0170-2PubMedGoogle Scholar
  23. Madrazo JA, Kelly DP: The PPAR trio: regulators of myocardial energy metabolism in health and disease. J Mol Cell Cardiol 2008, 44: 968–975. 10.1016/j.yjmcc.2008.03.021PubMedGoogle Scholar
  24. Chinetti-Gbaguidi G, Fruchart J-C, Staels B: Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy. Curr Opin Pharmacol 2005, 5: 177–183. 10.1016/j.coph.2004.11.004PubMedGoogle Scholar
  25. Wenz T: PGC-1α activation as a therapeutic approach in mitochondrial disease. Iubmb Life 2009, 61: 1051–1062. 10.1002/iub.261PubMedGoogle Scholar
  26. López-Lluch G, Irusta PM, Navas P, de Cabo R: Mitochondrial biogenesis and healthy aging. Exp Gerontol 2008, 43: 813–819. 10.1016/j.exger.2008.06.014PubMedPubMed CentralGoogle Scholar
  27. Pilegaard H, Saltin B, Neufer PD: Exercise induces transient transcriptional activation of the PGC-1α gene in human skeletal muscle. J Physiol 2003, 546: 851–858. 10.1113/jphysiol.2002.034850PubMedPubMed CentralGoogle Scholar
  28. Lira VA, Benton CR, Yan Z, Bonen A: PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab 2010, 299: E145-E161.PubMedPubMed CentralGoogle Scholar
  29. Corton JC, Brown-Borg HM: Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci 2005, 60: 1494–1509. 10.1093/gerona/60.12.1494PubMedGoogle Scholar
  30. Bastin J, Aubey F, Rötig A, Munnich A, Djouadi F: Activation of peroxisome proliferator-activated receptor pathway stimulates the mitochondrial respiratory chain and can correct deficiencies in patients’ cells lacking its components. J Clin Endocrinol Metab 2008, 93: 1433–1441. 10.1210/jc.2007-1701PubMedGoogle Scholar
  31. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J: Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 2006, 127: 1109–1122. 10.1016/j.cell.2006.11.013PubMedGoogle Scholar
  32. Lee SK, Lee JO, Kim JH, Kim N, You GY, Moon JW, Sha J, Kim SJ, Lee YW, Kang HJ, Park SH, Kim HS: Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARα induction in 3 T3-L1 preadipocytes. Cell Signal 2012, 24: 2329–2336. 10.1016/j.cellsig.2012.07.022PubMedGoogle Scholar
  33. Ogasahara S, Engel AG, Frens D, Mack D: Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci 1989, 86: 2379–2382. 10.1073/pnas.86.7.2379PubMedPubMed CentralGoogle Scholar
  34. Miles MV, Horn PS, Tang PH, Morrison JA, Miles L, DeGrauw T, Pesce AJ: Age-related changes in plasma coenzyme Q10 concentrations and redox state in apparently healthy children and adults. Clin Chim Acta 2004, 347: 139–144. 10.1016/j.cccn.2004.04.003PubMedGoogle Scholar
  35. Menke T, Niklowitz P, de Sousa G, Reinehr T, Andler W: Comparison of coenzyme Q10 plasma levels in obese and normal weight children. Clin Chim Acta 2004, 349: 121–127. 10.1016/j.cccn.2004.06.015PubMedGoogle Scholar
  36. Chew GT, Watts GF: Coenzyme Q10 and diabetic endotheliopathy: oxidative stress and the ‘recoupling hypothesis’. QJM 2004, 97: 537–548. 10.1093/qjmed/hch089PubMedGoogle Scholar
  37. McDonnell MG, Archbold GPR: Plasma ubiquinol/cholesterol ratios in patients with hyperlipidaemia, those with diabetes mellitus and in patients requiring dialysis. Clin Chim Acta 1996, 253: 117–126. 10.1016/0009-8981(96)06357-7PubMedGoogle Scholar
  38. Lim SC, Tan HH, Goh SK, Subramaniam T, Sum CF, Tan IK, Lee BL, Ong CN: Oxidative burden in prediabetic and diabetic individuals: evidence from plasma coenzyme Q10. Diabetic Med 2006, 23: 1344–1349. 10.1111/j.1464-5491.2006.01996.xPubMedGoogle Scholar
  39. El-ghoroury EA, Raslan HM, Badawy EA, El-Saaid GS, Agybi MH, Siam I, Salem SI: Malondialdehyde and coenzyme Q10 in platelets and serum in type 2 diabetes mellitus: correlation with glycemic control. Blood Coagul Fibrinolysis 2009, 20: 248–251. 210 10.1097/MBC.0b013e3283254549PubMedGoogle Scholar
  40. Menke T, Niklowitz P, Wiesel T, Andler W: Antioxidant level and redox status of coenzyme Q10 in the plasma and blood cells of children with diabetes mellitus type 1. Pediatr Diabetes 2008, 9: 540–545. 10.1111/j.1399-5448.2008.00389.xPubMedGoogle Scholar
  41. Silver MA, Langsjoen PH, Szabo S, Patil H, Zelinger A: Effect of atorvastatin on left ventricular diastolic function and ability of coenzyme Q10 to reverse that dysfunction. Am J Cardiol 2004, 94: 1306–1310. 10.1016/j.amjcard.2004.07.121PubMedGoogle Scholar
  42. Folkers K, Langsjoen P, Willis R, Richardson P, Xia LJ, Ye CQ, Tamagawa H: Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci 1990, 87: 8931–8934. 10.1073/pnas.87.22.8931PubMedPubMed CentralGoogle Scholar
  43. Bargossi AM, Battino M, Gaddi A, Fiorella PL, Grossi G, Barozzi G, Di Giulio R, Descovich G, Sassi S, Genova ML, Lenaz G: Exogenous CoQ10 preserves plasma ubiquinone levels in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Int J Clin Lab Res 1994, 24: 171–176. 10.1007/BF02592449PubMedGoogle Scholar
  44. Troseid M, Henriksen OA, Lindal S: Statin-associated myopathy with normal creatine kinase levels. Case report from a Norwegian family. APMIS 2005, 113: 635–637. 10.1111/j.1600-0463.2005.apm_270.xPubMedGoogle Scholar
  45. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JD: Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002, 137: 581–585. 10.7326/0003-4819-137-7-200210010-00009PubMedGoogle Scholar
  46. Caso G, Kelly P, McNurlan MA, Lawson WE: Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol 2007, 99: 1409–1412. 10.1016/j.amjcard.2006.12.063PubMedGoogle Scholar
  47. Folkers K, Vadhanavikit S, Mortensen SA: Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proc Natl Acad Sci 1985, 82: 901–904. 10.1073/pnas.82.3.901PubMedPubMed CentralGoogle Scholar
  48. Oh J, Ban MR, Miskie BA, Pollex RL, Hegele RA: Genetic determinants of statin intolerance. Lipids Health Dis 2007, 6: 7. 10.1186/1476-511X-6-7PubMedPubMed CentralGoogle Scholar
  49. Vladutiu GD, Simmons Z, Isackson PJ, Tarnopolsky M, Peltier WL, Barboi AC, Sripathi N, Wortmann RL, Phillips PS: Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve 2006, 34: 153–162. 10.1002/mus.20567PubMedGoogle Scholar
  50. Tappel AL: Vitamin E and free radical peroxidation of lipids. Ann N Y Acad Sci 1972, 203: 12–28. 10.1111/j.1749-6632.1972.tb27851.xPubMedGoogle Scholar
  51. Stocker R, Bowry VW, Frei B: Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci 1991, 88: 1646–1650. 10.1073/pnas.88.5.1646PubMedPubMed CentralGoogle Scholar
  52. Shekelle P, Hardy ML, Coulter I, Udani J, Spar M, Oda K, Jungvig LK, Tu W, Suttorp MJ, Valentine D, Ramirez L, Shanman R, Newberry SJ: Effect of the supplemental use of antioxidants vitamin C, vitamin E, and coenzyme Q10 for the prevention and treatment of cancer. (Prepared by Southern California Evidence-based Practice Center under Contract No. 290–97–0001.) AHRQ Publication No. 04-E003. Rockville, MD: Agency for Healthcare Research and Quality; 2003.Google Scholar
  53. Sohal RS, Forster MJ: Coenzyme Q, oxidative stress and aging. Mitochondrion 2007, 7(Suppl):S103-S111.PubMedPubMed CentralGoogle Scholar
  54. Roginsky VA, Tashlitsky VN, Skulachev VP: Chain-breaking antioxidant activity of reduced forms of mitochondria-targeted quinones, a novel type of geroprotectors. Aging 2009, 1: 481–489.PubMedPubMed CentralGoogle Scholar
  55. Abdin AA, Hamouda HE: Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism. Neuropharmacol 2008, 55: 1340–1346. 10.1016/j.neuropharm.2008.08.033Google Scholar
  56. Tomasetti M, Littarru GP, Stocker R, Alleva R: Coenzyme Q10 enrichment decreases oxidative DNA damage in human lymphocytes. Free Radic Biol Med 1999, 27: 1027–1032. 10.1016/S0891-5849(99)00132-XPubMedGoogle Scholar
  57. Tomasetti M, Alleva R, Borghi B, Collins AR: In vivo supplementation with coenzyme Q10 enhances the recovery of human lymphocytes from oxidative DNA damage. FASEB J 2001, 15: 1425–1427.PubMedGoogle Scholar
  58. Modi K, Santani DD, Goyal RK, Bhatt PA: Effect of coenzyme Q10 on catalase activity and other antioxidant parameters in streptozotocin-induced diabetic rats. Biol Trace Elem Res 2006, 109: 25–34. 10.1385/BTER:109:1:025PubMedGoogle Scholar
  59. Fouad AA, Jresat I: Hepatoprotective effect of coenzyme Q10 in rats with acetaminophen toxicity. Environ Toxicol Pharmacol 2012, 33: 158–167. 10.1016/j.etap.2011.12.011PubMedGoogle Scholar
  60. Lee B-J, Huang Y-C, Chen S-J, Lin P-T: Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease. Nutrition 2012, 28: 250–255. 10.1016/j.nut.2011.06.004PubMedGoogle Scholar
  61. Seitz CS, Kleindienst R, Xu Q, Wick G: Coexpression of heat-shock protein 60 and intercellular-adhesion molecule-1 is related to increased adhesion of monocytes and T cells to aortic endothelium of rats in response to endotoxin. Lab Invest 1996, 74: 241–252.PubMedGoogle Scholar
  62. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003, 112: 1821–1830. 10.1172/JCI200319451PubMedPubMed CentralGoogle Scholar
  63. Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest 2005, 115: 1111–1119. 10.1172/JCI200525102PubMedPubMed CentralGoogle Scholar
  64. Milagro FI, Campion J, Martinez JA: Weight gain induced by high-fat feeding involves increased liver oxidative stress. Obesity 2006, 14: 1118–1123. 10.1038/oby.2006.128PubMedGoogle Scholar
  65. Shoelson SE, Herrero L, Naaz A: Obesity, inflammation, and insulin resistance. Gastroenterol 2007, 132: 2169–2180. 10.1053/j.gastro.2007.03.059Google Scholar
  66. Abedini A, Shoelson SE: Inflammation and obesity: stamping out insulin resistance? Immunol Cell Biol 2007, 85: 399–400. 10.1038/sj.icb.7100107PubMedGoogle Scholar
  67. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M: IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005, 11: 191–198. 10.1038/nm1185PubMedGoogle Scholar
  68. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE: Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005, 11: 183–190. 10.1038/nm1166PubMedPubMed CentralGoogle Scholar
  69. Bochud M, Marquant F, Marques-Vidal P-M, Vollenweider P, Beckmann JS, Mooser V, Paccaud F, Rousson V: Association between C-reactive protein and adiposity in women. J Clin Endocrinol Metab 2009, 94: 3969–3977. 10.1210/jc.2008-2428PubMedGoogle Scholar
  70. Lapice E, Maione S, Patti L, Cipriano P, Rivellese AA, Riccardi G, Vaccaro O: Abdominal adiposity is associated with elevated C-reactive protein independent of BMI in healthy nonobese people. Diabetes Care 2009, 32: 1734–1736. 10.2337/dc09-0176PubMedPubMed CentralGoogle Scholar
  71. Nijhuis J, Rensen SS, Slaats Y, van Dielen FM, Buurman WA, Greve JW: Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity 2009, 17: 2014–2018. 10.1038/oby.2009.113PubMedGoogle Scholar
  72. Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993, 259: 87–91. 10.1126/science.7678183PubMedGoogle Scholar
  73. Sethi JK, Hotamisligil GS: The role of TNF alpha in adipocyte metabolism. Semin Cell Dev Biol 1999, 10: 19–29. 10.1006/scdb.1998.0273PubMedGoogle Scholar
  74. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM: Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995, 95: 2409–2415. 10.1172/JCI117936PubMedPubMed CentralGoogle Scholar
  75. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB: The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 1995, 95: 2111–2119. 10.1172/JCI117899PubMedPubMed CentralGoogle Scholar
  76. El-Moselhy MA, Taye A, Sharkawi SS, El-Sisi SFI, Ahmed AF: The antihyperglycemic effect of curcumin in high fat diet fed rats. Role of TNF-α and free fatty acids. Food Chem Toxicol 2011, 49: 1129–1140. 10.1016/j.fct.2011.02.004PubMedGoogle Scholar
  77. Mehta NN, McGillicuddy FC, Anderson PD, Hinkle CC, Shah R, Pruscino L, Tabita-Martinez J, Sellers KF, Rickels MR, Reilly MP: Experimental Endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes 2010, 59: 172–181. 10.2337/db09-0367PubMedPubMed CentralGoogle Scholar
  78. Matarazzo S, Quitadamo MC, Mango R, Ciccone S, Novelli G, Biocca S: Cholesterol-lowering drugs inhibit lectin-like oxidized low-density lipoprotein-1 receptor function by membrane raft disruption. Mol Pharmacol 2012, 82: 246–254. 10.1124/mol.112.078915PubMedGoogle Scholar
  79. Bieghs V, Van Gorp PJ, Wouters K, Hendrikx T, Gijbels MJ, van Bilsen M, Bakker J, Binder CJ, Lutjohann D, Staels B, Hofker MH, Shiri-Sverdlov R: LDL receptor knock-out mice are a physiological model particularly vulnerable to study the onset of inflammation in non-alcoholic fatty liver disease. Plos One 2012, 7: e30668. 10.1371/journal.pone.0030668PubMedPubMed CentralGoogle Scholar
  80. Flock MR, Green MH, Kris-Etherton PM: Effects of adiposity on plasma lipid response to reductions in dietary saturated fatty acids and cholesterol. Advances in Nutrition 2011, 2: 261–274. 10.3945/an.111.000422PubMedPubMed CentralGoogle Scholar
  81. Henninger DD, Gerritsen ME, Granger DN: Low-density lipoprotein receptor knockout mice exhibit exaggerated microvascular responses to inflammatory stimuli. Cir Res 1997, 81: 274–281. 10.1161/01.RES.81.2.274Google Scholar
  82. Zabalawi M, Bhat S, Loughlin T, Thomas MJ, Alexander E, Cline M, Bullock B, Willingham M, Sorci-Thomas MG: Induction of fatal inflammation in LDL receptor and ApoA-I double-knockout mice fed dietary fat and cholesterol. Am J Pathol 2003, 163: 1201–1213. 10.1016/S0002-9440(10)63480-3PubMedPubMed CentralGoogle Scholar
  83. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK: Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice. J Clin Invest 2000, 106: 523–531. 10.1172/JCI10370PubMedPubMed CentralGoogle Scholar
  84. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK: The peroxisome proliferator-activated receptor-[gamma] is a negative regulator of macrophage activation. Nature 1998, 391: 79–82. 10.1038/34178PubMedGoogle Scholar
  85. Cuzzocrea S, Mazzon E, Di Paola R, Peli A, Bonato A, Britti D, Genovese T, Muia C, Crisafulli C, Caputi AP: The role of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in the regulation of acute inflammation. J Leukoc Biol 2006, 79: 999–1010. 10.1189/jlb.0605341PubMedGoogle Scholar
  86. Schmelzer C, Lorenz G, Rimbach G, Döring F: In vitro effects of the reduced form of coenzyme Q10 on secretion levels of TNF-α and chemokines in response to LPS in the human monocytic cell line THP-1. J Nutr Biochem 2009, 44: 62–66. 10.3164/jcbn.08-182Google Scholar
  87. Schmelzer C, Lorenz G, Rimbach G, Döring F: Influence of Coenzyme Q10 on release of pro-inflammatory chemokines in the human monocytic cell line THP-1. BioFactors 2007, 31: 211–217. 10.1002/biof.5520310308PubMedGoogle Scholar
  88. Carmona MC, Lefebvre P, Lefebvre B, Galinier A, Benani A, Jeanson Y, Louche K, Flajollet S, Ktorza A, Dacquet C, Penicaud L, Casteilla L: Coadministration of coenzyme Q prevents rosiglitazone-induced adipogenesis in ob/ob mice. Int J Obes 2009, 33: 204–211. 10.1038/ijo.2008.265Google Scholar
  89. Sohet FM, Neyrinck AM, Pachikian BD, de Backer FC, Bindels LB, Niklowitz P, Menke T, Cani PD, Delzenne NM: Coenzyme Q10 supplementation lowers hepatic oxidative stress and inflammation associated with diet-induced obesity in mice. Biochem Pharmacol 2009, 78: 1391–1400. 10.1016/j.bcp.2009.07.008PubMedGoogle Scholar
  90. Schmelzer C, Kitano M, Hosoe K, Doring F: Ubiquinol affects the expression of genes involved in PPARalpha signalling and lipid metabolism without changes in methylation of CpG promoter islands in the liver of mice. J Clin Biochem Nutr 2012, 50: 119–126. 10.3164/jcbn.11-19PubMedPubMed CentralGoogle Scholar
  91. Schmelzer C, Kubo H, Mori M, Sawashita J, Kitano M, Hosoe K, Boomgaarden I, Döring F, Higuchi K: Supplementation with the reduced form of Coenzyme Q10 decelerates phenotypic characteristics of senescence and induces a peroxisome proliferator-activated receptor-α gene expression signature in SAMP1 mice. Mol Nutr Food Res 2010, 54: 805–815.PubMedGoogle Scholar
  92. Kunitomo M, Yamaguchi Y, Kagota S, Otsubo K: Beneficial effect of coenzyme Q10 on increased oxidative and nitrative stress and inflammation and individual metabolic components developing in a rat model of metabolic syndrome. J Pharmacol Sci 2008, 107: 128–137. 10.1254/jphs.FP0072365PubMedGoogle Scholar
  93. Ozdogan S, Kaman D, Simsek BC: Effects of coenzyme Q10 and alpha-lipoic acid supplementation in fructose fed rats. J Clin Biochem Nutr 2012, 50: 145–151. full_textPubMedPubMed CentralGoogle Scholar
  94. Hamilton SJ, Chew GT, Watts GF: Coenzyme Q10 improves endothelial dysfunction in statin-treated type 2 diabetic patients. Diabetes Care 2009, 32: 810–812. 10.2337/dc08-1736PubMedPubMed CentralGoogle Scholar
  95. Tsai KL, Huang YH, Kao CL, Yang DM, Lee HC, Chou HY, Chen YC, Chiou GY, Chen LH, Yang YP, Chiu TH, Tsai CS, Ou HC, Chiou SH: A novel mechanism of coenzyme Q10 protects against human endothelial cells from oxidative stress-induced injury by modulating NO-related pathways. J Nutr Biochem 2012, 23: 458–468. 10.1016/j.jnutbio.2011.01.011PubMedGoogle Scholar
  96. Tiano L, Belardinelli R, Carnevali P, Principi F, Seddaiu G, Littarru GP: Effect of coenzyme Q10 administration on endothelial function and extracellular superoxide dismutase in patients with ischaemic heart disease: a double-blind, randomized controlled study. Eur Heart J 2007, 28: 2249–2255. 10.1093/eurheartj/ehm267PubMedGoogle Scholar
  97. Yamagami T, Iwamoto Y, Folkers K, Blomqvist CG: Reduction by coenzyme Q10 of hypertension induced by deoxycorticosterone and saline in rats. Int J Vitam Nutr Res 1974, 44: 487–496.PubMedGoogle Scholar
  98. Iwamoto Y, Yamagami T, Folkers K, Blomqvist CG: Deficiency of coenzyme Q10 in hypertensive rats and reduction of deficiency by treatment with coenzyme Q10. Biochem Biophys Res Commun 1974, 58: 743–748. 10.1016/S0006-291X(74)80480-8PubMedGoogle Scholar
  99. Murad LB, Guimaraes MR, Vianna LM: Effects of decylubiquinone (coenzyme Q10 analog) supplementation on SHRSP. BioFactors 2007, 30: 13–18. 10.1002/biof.5520300102PubMedGoogle Scholar
  100. Rosenfeldt FL, Haas SJ, Krum H, Hadj A, Ng K, Leong JY, Watts GF: Coenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trials. J Hum Hypertens 2007, 21: 297–306.PubMedGoogle Scholar
  101. Young JM, Florkowski CM, Molyneux SL, McEwan RG, Frampton CM, Nicholls MG, Scott RS, George PM: A randomized, double-blind, placebo-controlled crossover study of coenzyme q10 therapy in hypertensive patients with the metabolic syndrome. Am J Hypertens 2012, 25: 261–270. 10.1038/ajh.2011.209PubMedGoogle Scholar
  102. Digiesi V, Cantini F, Oradei A, Bisi G, Guarino GC, Brocchi A, Bellandi F, Mancini M, Littarru GP: Coenzyme Q10 in essential hypertension. Mol Aspects Med 1994, 15(Suppl):s257-s263.PubMedGoogle Scholar
  103. Pepe S, Marasco SF, Haas SJ, Sheeran FL, Krum H, Rosenfeldt FL: Coenzyme Q10 in cardiovascular disease. Mitochondrion 2007, 7(Suppl):S154-S167.PubMedGoogle Scholar
  104. Lonnrot K, Porsti I, Alho H, Wu X, Hervonen A, Tolvanen JP: Control of arterial tone after long-term coenzyme Q10 supplementation in senescent rats. Br J Pharmacol 1998, 124: 1500–1506. 10.1038/sj.bjp.0701970PubMedPubMed CentralGoogle Scholar
  105. Kumar A, Kaur H, Devi P, Mohan V: Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. Pharmacol Ther 2009, 124: 259–268. 10.1016/j.pharmthera.2009.07.003PubMedGoogle Scholar
  106. Vogt AM, Kübler W: Heart failure: is there an energy deficit contributing to contractile dysfunction? Basic Res Cardiol 1998, 93: 1–10. 10.1007/s003950050055PubMedGoogle Scholar
  107. Folkers K, Littarru GP, Ho L, Runge TM, Havanonda S, Cooley D: Evidence for a deficiency of coenzyme Q10 in human heart disease. Int Z Vitaminforsch 1970, 40: 380–390.PubMedGoogle Scholar
  108. Langsjoen PH, Folkers K: A six-year clinical study of therapy of cardiomyopathy with coenzyme Q10. Int J Tissue React 1990, 12: 169–171.PubMedGoogle Scholar
  109. Langsjoen PH, Langsjoen A, Willis R, Folkers K: Treatment of hypertrophic cardiomyopathy with coenzyme Q10. Mol Aspects Med 1997, 18(Suppl):S145-S151.PubMedGoogle Scholar
  110. Ohhara H, Kanaide H, Yoshimura R, Okada M, Nakamura M: A protective effect of coenzyme Q10 on ischemia and reperfusion of the isolated perfused rat heart. J Mol Cell Cardiol 1981, 13: 65–74.PubMedGoogle Scholar
  111. Hano O, Thompson-Gorman SL, Zweier JL, Lakatta EG: Coenzyme Q10 enhances cardiac functional and metabolic recovery and reduces Ca2+ overload during postischemic reperfusion. Am J Physiol 1994, 266: H2174-H2181.PubMedGoogle Scholar
  112. Niibori K, Wroblewski KP, Yokoyama H, Crestanello JA, Whitman GJ: Bioenergetic effect of liposomal coenzyme Q10 on myocardial ischemia reperfusion injury. BioFactors 1999, 9: 307–313. 10.1002/biof.5520090228PubMedGoogle Scholar
  113. Combs AB, Choe JY, Truong DH, Folkers K: Reduction by coenzyme Q10 of the acute toxicity of adriamycin in mice. Res Commun Chem Pathol Pharmacol 1977, 18: 565–568.PubMedGoogle Scholar
  114. Shinozawa S, Etowo K, Araki Y, Oda T: Effect of coenzyme Q10 on the survival time and lipid peroxidation of adriamycin (doxorubicin) treated mice. Acta Med Okayama 1984, 38: 57–63.PubMedGoogle Scholar
  115. Kucharska J, Braunova Z, Ulicna O, Zlatos L, Gvozdjakova A: Deficit of coenzyme Q in heart and liver mitochondria of rats with streptozotocin-induced diabetes. Physiol Res 2000, 49: 411–418.PubMedGoogle Scholar
  116. Gvozdjakova A, Kucharska J, Mizera S, Braunova Z, Schreinerova Z, Schramekova E, Pechan I, Fabian J: Coenzyme Q10 depletion and mitochondrial energy disturbances in rejection development in patients after heart transplantation. BioFactors 1999, 9: 301–306. 10.1002/biof.5520090227PubMedGoogle Scholar
  117. Eriksson JG, Forsen TJ, Mortensen SA, Rohde M: The effect of coenzyme Q10 administration on metabolic control in patients with type 2 diabetes mellitus. BioFactors 1999, 9: 315–318. 10.1002/biof.5520090229PubMedGoogle Scholar
  118. Henriksen JE, Andersen CB, Hother-Nielsen O, Vaag A, Mortensen SA, Beck-Nielsen H: Impact of ubiquinone (coenzyme Q10) treatment on glycaemic control, insulin requirement and well-being in patients with Type 1 diabetes mellitus. Diabet Med 1999, 16: 312–318. 10.1046/j.1464-5491.1999.00064.xPubMedGoogle Scholar
  119. Sena CM, Nunes E, Gomes A, Santos MS, Proença T, Martins MI, Seiça RM: Supplementation of coenzyme Q10 and α-tocopherol lowers glycated hemoglobin level and lipid peroxidation in pancreas of diabetic rats. Nutr Res 2008, 28: 113–121. 10.1016/j.nutres.2007.12.005PubMedGoogle Scholar
  120. Repa JJ, Mangelsdorf DJ: The liver X receptor gene team: potential new players in atherosclerosis. Nat Med 2002, 8: 1243–1248. 10.1038/nm1102-1243PubMedGoogle Scholar
  121. Seo JB, Moon HM, Kim WS, Lee YS, Jeong HW, Yoo EJ, Ham J, Kang H, Park M-G, Steffensen KR, Stulnig TM, Gustafsson JÅ, Park SD, Kim JB: Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferator-activated receptor γ expression. Mol Cell Biol 2004, 24: 3430–3444. 10.1128/MCB.24.8.3430-3444.2004PubMedPubMed CentralGoogle Scholar
  122. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P: Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 2003, 9: 213–219. 10.1038/nm820PubMedGoogle Scholar
  123. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ: Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 1998, 93: 693–704. 10.1016/S0092-8674(00)81432-4PubMedGoogle Scholar
  124. Ide T, Shimano H, Yoshikawa T, Yahagi N, Amemiya-Kudo M, Matsuzaka T, Nakakuki M, Yatoh S, Iizuka Y, Tomita S, Ohashi K, Takahashi A, Sone H, Gotoda T, Osuga J-i, Ishibashi S, Yamada N: Cross-talk between peroxisome proliferator-activated receptor (PPAR) α and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol Endocrinol 2003, 17: 1255–1267. 10.1210/me.2002-0191PubMedGoogle Scholar
  125. Schmelzer C, Okun JG, Haas D, Higuchi K, Sawashita J, Mori M, Doring F: The reduced form of coenzyme Q10 mediates distinct effects on cholesterol metabolism at the transcriptional and metabolite level in SAMP1 mice. Iubmb Life 2010, 62: 812–818. 10.1002/iub.388PubMedGoogle Scholar
  126. Bentinger M, Tekle M, Dallner G, Brismar K, Gustafsson J, Steffensen K, Catrina SB: Influence of liver-X-receptor on tissue cholesterol, coenzyme Q and dolichol content. Molec Membrane Biol 2012, 29: 299–308. 10.3109/09687688.2012.694484Google Scholar
  127. Quiles JL, Ochoa JJ, Battino M, Gutierrez-Rios P, Nepomuceno EA, Frias ML, Huertas JR, Mataix J: Life-long supplementation with a low dosage of coenzyme Q10 in the rat: effects on antioxidant status and DNA damage. BioFactors 2005, 25: 73–86. 10.1002/biof.5520250109PubMedGoogle Scholar
  128. Quiles JL, Ochoa JJ, Huertas JR, Mataix J: Coenzyme Q supplementation protects from age-related DNA double-strand breaks and increases lifespan in rats fed on a PUFA-rich diet. Exp Gerontol 2004, 39: 189–194. 10.1016/j.exger.2003.10.002PubMedGoogle Scholar
  129. Safwat GM, Pisano S, D'Amore E, Borioni G, Napolitano M, Kamal AA, Ballanti P, Botham KM, Bravo E: Induction of non-alcoholic fatty liver disease and insulin resistance by feeding a high-fat diet in rats: does coenzyme Q monomethyl ether have a modulatory effect? Nutrition 2009, 25: 1157–1168. 10.1016/j.nut.2009.02.009PubMedGoogle Scholar
  130. Sutken E, Aral E, Ozdemir F, Uslu S, Alatas O, Colak O: Protective role of melatonin and coenzyme Q10 in ochratoxin A toxicity in rat liver and kidney. Int J Toxicol 2007, 26: 81–87. 10.1080/10915810601122893PubMedGoogle Scholar
  131. Bello RI, Gomez-Diaz C, Buron MI, Alcain FJ, Navas P, Villalba JM: Enhanced anti-oxidant protection of liver membranes in long-lived rats fed on a coenzyme Q10-supplemented diet. Exp Gerontol 2005, 40: 694–706. 10.1016/j.exger.2005.07.003PubMedGoogle Scholar
  132. Cornier M-A, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH: The metabolic syndrome. Endocrine Rev 2008, 29: 777–822. 10.1210/er.2008-0024Google Scholar
  133. Mehmetoglu I, Yerlikaya FH, Kurban S: Correlation between vitamin A, E, coenzyme Q-10 and degree of insulin resistance in obese and non-obese subjects. J Clin Biochem Nutr 2011, 49: 159–163. 10.3164/jcbn.11-08PubMedPubMed CentralGoogle Scholar
  134. Bour S, Carmona MC, Galinier A, Caspar-Bauguil S, Van Gaal L, Staels B, Penicaud L, Casteilla L: Coenzyme Q as an antiadipogenic factor. Antioxid Redox Signal 2011, 14: 403–413. 10.1089/ars.2010.3350PubMedGoogle Scholar
  135. Foretz M, Pacot C, Dugail I, Lemarchand P, Guichard C, le Lièpvre X, Berthelier-Lubrano C, Spiegelman B, Kim JB, Ferré P, Foufelle F: ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Mol Cell Biol 1999, 19: 3760–3768.PubMedPubMed CentralGoogle Scholar
  136. Murphy MP, Smith RA: Drug delivery to mitochondria: the key to mitochondrial medicine. Adv Drug Deliv Rev 2000, 41: 235–250. 10.1016/S0169-409X(99)00069-1PubMedGoogle Scholar
  137. Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, Sammut IA: Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J 2005, 19: 1088–1095. 10.1096/fj.05-3718comPubMedGoogle Scholar
  138. Lowes DA, Thottakam BM, Webster NR, Murphy MP, Galley HF: The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. Free Radic Biol Med 2008, 45: 1559–1565. 10.1016/j.freeradbiomed.2008.09.003PubMedGoogle Scholar
  139. Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RAJ, Cochemé HM, Murphy MP, Dominiczak AF: Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension 2009, 54: 322–328. 10.1161/HYPERTENSIONAHA.109.130351PubMedGoogle Scholar
  140. Vergeade A, Mulder P, Vendeville-Dehaudt C, Estour F, Fortin D, Ventura-Clapier R, Thuillez C, Monteil C: Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: prevention by the targeted antioxidant MitoQ. Free Radical Biol Med 2010, 49: 748–756. 10.1016/j.freeradbiomed.2010.05.024Google Scholar
  141. Chacko BK, Srivastava A, Johnson MS, Benavides GA, Chang MJ, Ye Y, Jhala N, Murphy MP, Kalyanaraman B, Darley-Usmar VM: Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis. J Hepatol 2011, 54: 153–163.Google Scholar
  142. Mercer JR, Yu E, Figg N, Cheng K-K, Prime TA, Griffin JL, Masoodi M, Vidal-Puig A, Murphy MP, Bennett MR: The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice. Free Radical Biol Med 2012, 52: 841–849. 10.1016/j.freeradbiomed.2011.11.026Google Scholar
  143. Kutz K, Drewe J, Vankan P: Pharmacokinetic properties and metabolism of idebenone. J Neurol 2009, 256(Suppl 1):31–35.PubMedGoogle Scholar
  144. Sugiyama Y, Fujita T, Matsumoto M, Okamoto K, Imada I: Effects of idebenone (CV-2619) and its metabolites on respiratory activity and lipid peroxidation in brain mitochondria from rats and dogs. J Pharmacobiodyn 1985, 8: 1006–1017. 10.1248/bpb1978.8.1006PubMedGoogle Scholar
  145. Suno M, Nagaoka A: Inhibition of lipid peroxidation by idebenone in brain mitochondria in the presence of succinate. Arch Gerontol Geriatr 1989, 8: 291–297. 10.1016/0167-4943(89)90010-1PubMedGoogle Scholar
  146. Suno M, Shibota M, Nagaoka A: Effects of idebenone on lipid peroxidation and hemolysis in erythrocytes of stroke-prone spontaneously hypertensive rats. Arch Gerontol Geriatr 1989, 8: 307–311. 10.1016/0167-4943(89)90012-5PubMedGoogle Scholar

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