HD administered to rats induced an increment in serum cholesterol and triacylglycerols (Figure 1A). These results are consistent with previous studies [9, 10]. As expected, when ATV was administered, cholesterol and triacylglycerols showed a dose dependent decrement (p < 0.05). Supplementation with CoQ10 increased the effects of ATV on cholesterol levels. Rats with HD showed a slight increased concentration of serum triacylglycerols. The administration of ATV did not reduce these TAG levels, however, all values were minor when CoQ10 was supplemented (Figure 1C, D).
In our study it was observed a significant diminution of serum cholesterol in rats that received ATV + CoQ10 in comparison with those groups that did not receive CoQ10. These results support a better hypolipidemic effect of ATV in the presence of CoQ10. This improvement in the effect of ATV by CoQ10 has already been reported in Guinea pigs [10, 11].
HDL-C showed a significant decrease in the HD group. The administration of ATV to HD rats did not increase HDL-C values but kept them similar to those observed in CD group. However, HDL-C values were higher in groups CD + CoQ10, HD + CoQ10 and CD + ATV2 + CoQ10 compared to CD without CoQ10 supplementation (Figure 1E, F). These results confirm the beneficial effect of ATV on HDL-C levels and even the more beneficial effect of CoQ10 supplementation on at least in groups CD + CoQ10, HD + CoQ10 and CD + ATV2 + CoQ10.
It is well known that statins inhibit cholesterol biosynthesis in the liver, decrease the intracellular cholesterol content, augment low density lipoprotein-receptor (LDL-R) synthesis as well as the cholesterol uptake by the liver, and diminish serum total cholesterol concentration . In addition, statins increment HDL-C levels throughout an increase of apoprotein A synthesis in the liver  and a reduced activity of cholesterol ester transfer protein (CETP).
Mabuchi et al.  reported that co-administration of ATV-CoQ10, favored a significant increase of HDL-C in hypercholesterolemic patients. Singh et al.  observed an important increment of HDL-C in patients that received CoQ10. However, it has been reported no increase in HDL-C in patients that received simvastatin and CoQ10. Nevertheless, it is not clear how is that synergistic effect of CoQ10 on ATV action. It is well known that CoQ10 and cholesterol are synthesized by the same pathway and that high ATV doses produce a significant decrement in CoQ10 levels in plasma [14, 15] and this decrement in serum CoQ10 is related direct or indirectly to the potential liver harm produced by the statin treatment . On the other hand, CoQ10 administration may inhibit the expression of the apo A-I receptor, increasing apoprotein A-I and increasing HDL-C levels .
Our results show that rats that received atorvastatin (0.2 mg/day) and CoQ10 had lower levels of serum glucose than the same group without CoQ10 (Figure 1G, H). In addition, CoQ10 regulates glucose levels throughout a diminution of oxidative stress . On the other hand, other reports have shown that ATV lowers serum cholesterol, increases glucose blood levels and raises insulin resistance . These data altogether suggest that co-administration of CoQ10 and ATV improves glucose metabolism in the hypercholesterolemic state.
Some reports indicate that CoQ10 administration improves pancreatic beta cells function, increases insulin sensitivity and preserves the mitochondrial function in the pancreas . Moreover, CoQ10 diminishes lipoperoxidation and raises glucose uptake. These results suggest that CoQ10 improves glucose metabolism in hypercholesterolemia under atorvastatin treatment.
It was also observed in ATV-treated rats an increment in ALT and AST serum activity. Previous studies have also shown an increase in serum aminotransferases (ALT y AST) in rats that received HD and ATV [20, 21]; these results were related to liver damage. In accordance with these results, other animal models with hypercaloric diet are predisposed to hyperlipidemia and liver steatosis [21, 22]. On the other hand, a study employing ATV in rats did not show change in the activity of serum aminotransferases .
The high serum aminotransferases levels in rats with cholesterol-rich diet are related to liver damage. This harm is due to membrane damage in hepatocytes which produces a lessened antioxidant and detoxification capacity of the liver . Other studies have reported higher activity of transaminases produced by statin administration to rats [21, 22]. On the contrary, our study showed a slight decrement of AST and ALT activity in ATV-CoQ10, treated animals compared with those that received only ATV. Also, Mabuchi et al.  observed a diminution of AST and ALT in patients treated with ATV and CoQ10. Moreover, Abbas and Sakr  reported a diminution of AST and ALT activity in Guinea pigs that received simvastatin-CoQ10, comparing with animals that only received simvastatin. All these results together may assign a protector effect of CoQ10 on the hepatocytes of rats fed a cholesterol-rich diet.
In our study, it was observed that ATV lessened cholesterol and triacylglycerol concentration in the liver in a dose-dependent manner in hypercholesterolemic rats. Several reports suggest that this increment induced by HD contributes to the liver steatosis, as well as the dietary fatty acids and cholesterol promote the lipid accumulation in the hepatocytes. These cells have receptors for the transcription factor PPAR-α, allowing fatty acid oxidation in mitochondria, microsomes and peroxisomes . As a result, fatty acids oxidation products (hydrogen peroxide, oxygen superoxide and lipid peroxides) are produced and induce lipid peroxidation and oxidative stress .
Several studies have shown that a cholesterol-rich diet given to rats produce a fatty liver, hypertrophy of the liver and macroscopic alterations [25, 26] as a consequence of hepatocyte cholesterol saturation; the novo cholesterol synthesis lowers and consequently it is produced a diminished uptake of LDL by its receptors. Results from other studies show a lower activity of HMG-CoA reductase and lower expression of LDL receptors in the liver from rats fed a high fat diet . Our study showed a significant decrease of cholesterol and triacylglycerol levels in the liver of animals treated with ATV and CoQ10, compared with those rats that only received ATV. These results are in coincidence with other reports  that suggest CoQ10 improves the hypolipemiant action of statins. As we already mentioned it is not currently known the mechanism by which CoQ10 increases statins action. Some studies suggest CoQ10 influences the negative feedback of hepatic cholesterol. Moreover, cholesterol metabolism in the liver is mediated by lanosterol 14α demethylase (CYP51) throughout the sterol regulatory binding proteins (SREBPs) [28, 29]. Previous reports studying the effect of the reduced form of CoQ10 on the liver cholesterol metabolism, showed an antagonistic action on the ligand binding to X receptor (LXR) . Liver LXRs induce SREBP-1c, a transcription factor that controls the expression of several genes involved in cholesterol biosynthesis and its reverse transport. On the other hand, the amount of dietary cholesterol to be absorbed at the intestine is controlled by a transporter family (ABC), localized at the enterocyte membrane. These proteins pour out cholesterol from the enterocytes to the intestine lumen. The hydroxyl group of the reduced form of CoQ10 is important for this antagonistic action on ABC transporter genes throughout the LXR ligand . This mechanism may explain the cholesterol diminution in serum and liver observed in all animals that received ATV and CoQ10 in our study.
It is generally accepted that a cholesterol-rich diet produces structural mitochondrial alteration in the liver and higher production of reactive oxygen species (ROS) with hepatocellular damage [31, 32]. Electron microscope studies in rats with non-alcoholic fatty liver, show scarce mitochondria, higher in size, deformed, hypodense, with paracrystaline inclusions, hepatosteatosis and altered fatty acid oxidation . In our study HD produced a lower respiratory control. Other authors suggest that a high-lipid diet induce deterioration of complex I (NAD: ubiquinone oxidoreductase) and II (succinate dehydrogenase) of the mitochondrial chain . Other reports suggest that statins like pravastatin lessen the mitochondrial respiratory control affecting complex I and IV (cytochrome c oxidase) in skeletal muscle [33, 34]. In addition, simvastatin induces myotube atrophy and cell loss associated with impaired ADP-stimulated maximal mitochondrial respiratory capacity, mitochondrial oxidative stress . It is known that ATV reduces the cholesterol-phospholipid ratio in cellular membrane, raising its fluidity and the activity of ATPase Na+/K+. All these modifications in cellular membrane affect the activity of participating enzymes of the mitochondrial electron transport chain with probable alteration of its bioenergetic function. Our results support that the mitochondrial respiration diminution observed in animals treated with ATV can be attributed to lower levels of CoQ10.
The mitochondrial respiratory chain and particularly complex I and complex III (ubiquinone:cytochrome c oxidoreductase) are able to produce an anion superoxide from oxygen. In hepatocytes from normal rats this is a tenuous production that doesn’t interfere with the respiratory chain activity, but is functioning as a mitochondrial protective antioxidant system. On the other hand, CoQ10 is an invaluable component of the mitochondrial respiratory chain [36, 37] and a diminution in its availability affects for sure the energetic metabolism. It is known that the administration of CoQ10 and simvastatin increased the activity of complex I in cardiomyocytes but decreased with simvastatin alone. On the other hand, there are evidences suggesting that the significant decrease in ATP concentration in simvastatin-treated rats was due to CoQ10 deficiency . Our results show a higher mitochondrial RC in all groups that received ATV and CoQ10. On the same way, Kimura et al.  communicated the increase in muscle fibers contraction in rats that received CoQ10 due to improvement of cell membrane. A study suggests CoQ10 may reduce symptoms related to heart failure and increased energy production in heart muscle . Statins sometimes cause muscle pain and oral CoQ10 might reduce this pain [40, 41].
In our study we observed that ATV decreased mitochondrial respiration but ATV and CoQ10 improved mitochondrial function using succinate as substrate. Statins have been associated with a reduction in serum and muscle tissue coenzyme Q10 levels that may play a role in statin-induced myopathy. Aged people appear to be more susceptible to coenzyme Q10 deficiency. Athletes also require the most efficient oxygen consumption by mitochondria for their performance, and are more susceptible to CoQ10 deficiency. However, there is not a general opinion regarding the effectiveness of CoQ10 supplementation. It seems that those that would gain the major benefit from this supplementation are the hypercholesterolemic patients.