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Fibrates and statins lead worldwide prescriptions of lipid-lowering drugs, whose consumption is increasing considerably due to the growing incidence of dyslipidemias, particularly in high-income areas. Consequently, these chemicals are frequently found in aquatic environments, usually closer to highly urbanized and populated areas, reaching the water systems primarily through waste-water treatment plant (WWTP) effluents. Despite that, the knowledge regarding the effects caused by fibrates and statins in fish, namely in liver lipid metabolism and blood-related parameters, is still very limited. There is yet no standardized fish model for testing the effects of those drugs. However, experimental evidence suggests that the mechanisms of action (MoA) of fibrates and statins are fairly similar to those observed in humans, which makes these aquatic organisms viable alternatives for toxicological and mechanistic studies. This graphical review serves as a state point regarding the potential use of fish as a model for the study of hypolipidemic compounds, addressing (I) the current state of aquatic pollution caused by statins and fibrates, (II) the experimental designs used in the literature to assess effects on fish, (III) the liver metabolism and blood effects caused by exposure to fibrates and statins, as well as (IV) the MoA of both drugs. It further focuses on the current and future benefits of establishing a standardized fish model(s) for testing hypolipidemic drugs. [Display omitted] • Fibrate and statin water contamination is increasing worldwide. • The study of dyslipidemic effects caused by fibrates and statins in fish is still very limited. • Fibrates and statin effects in humans are very similar to those reported in fish. • Fish are promising in vivo model(s) for testing new hypolipidemic chemicals. [ABSTRACT FROM AUTHOR]

Introduction Hyperlipidemia is the most common form of dyslipidemia, which is the key risk factor for cardiovascular disease and stroke. The development of effective and safe drug treatments for hyperlipidemia has been proven challenging. Methods In this study, taking advantage of the transparency of larval zebrafish, we developed a zebrafish hyperlipidemia model for drug screening and efficacy assessment. Zebrafish at 5 d.p.f (days post fertilization) were fed with 0.1% egg yolk for 48 h (hours), followed by drug treatment for 24 h or 48 h. Tested drugs were administered into the zebrafish by direct soaking. Drug effect was evaluated based on quantitative analysis of Oil Red O (ORO) in zebrafish vena caudalis. Results All 5 human hypolipidemic drugs (simvastatin, lovastatin, ezetimibe, bezafibrate and hyodesoxycholic acid) showed significant hypolipidemic effects ( p < 0.01) in a dose-dependent manner in the zebrafish hyperlipidemia model. 'We also found a well-known Chinese tea Pu-erh tea significantly reduced lipids in this model ( p < 0.001 and p < 0.01). Discussion Our results demonstrate that the zebrafish hyperlipidemia model developed and validated in this study could be used for in vivo hyperlipidemia studies and drug screening and for assessing hypolipidemic drugs with different mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Statins and fibrates can cause myopathy. To further understand the causes of the damage we performed a proteome analysis in fast-twitch skeletal muscle of rats chronically treated with different hypolipidemic drugs. The proteomic maps were obtained from extensor digitorum longus (EDL) muscles of rats treated for 2-months with 10mg/kg atorvastatin, 20mg/kg fluvastatin, 60mg/kg fenofibrate and control rats. The proteins differentially expressed were identified by mass spectrometry and further analyzed by immunoblot analysis. We found a significant modification in 40 out of 417 total spots analyzed in atorvastatin treated rats, 15 out of 436 total spots in fluvastatin treated rats and 21 out of 439 total spots in fenofibrate treated rats in comparison to controls. All treatments induced a general tendency to a down-regulation of protein expression; in particular, atorvastatin affected the protein pattern more extensively with respect to the other treatments. Energy production systems, both oxidative and glycolytic enzymes and creatine kinase, were down-regulated following atorvastatin administration, whereas fenofibrate determined mostly alterations in glycolytic enzymes and creatine kinase, oxidative enzymes being relatively spared. Additionally, all treatments resulted in some modifications of proteins involved in cellular defenses against oxidative stress, such as heat shock proteins, and of myofibrillar proteins. These results were confirmed by immunoblot analysis. In conclusions, the proteomic analysis showed that either statin or fibrate administration can modify the expression of proteins essential for skeletal muscle function suggesting potential mechanisms for statin myopathy. [Copyright &y& Elsevier]

Abstract: This review focuses on the non-statin strategies for the treatment of hyperlipidemias in humans. Even if statins remain the major hypolipidemic drugs at present, an increasing number of patients that are treated with statins raises as well the numbers of patients suffering from side effects or not responding well to the therapy. Thus, development of novel approaches to battle the world epidemics of hyperlipidemia remains relevant. The non-statin strategies include the decrease of cholesterol absorption from the diet, lowering the atherogenic lipoprotein release and increasing HDL levels, or increasing elimination of cholesterol by bile acid binding. Representative non-statin drugs that are on the market or are in development phases are described herein in comparison to statins. In addition to 3β-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), as the major regulatory enzyme of cholesterol synthesis that is the target of statins, some other enzymes of this multi-step pathway represent perspective targets for the development of novel hypolipidemics. None of these inhibitors are currently approved for use in humans. We describe the characteristics of the later enzymes of cholesterol synthesis, starting from the squalene synthase step. Inhibitors of these enzymes are critically evaluated, particularly concerning safety in humans (teratogenic potential, toxicity, and other side effects) and their hypolipidemic effects compared to the statins. Since only a limited number of publications discuss the non-statin approaches for the treatment of hyperlipidemias, this review represents a valuable up-to date summary, with a take-home message, that novel approaches deserve more attention in the future, irrespective of the success of statins. [Copyright &y& Elsevier]

Abstract: Background/aim: Hepatic bile acid synthesis is the main mechanism whereby the organism can degrade cholesterol. Plasma levels of 7α-hydroxy-4-cholesten-3-one have been reported to reflect bile acid synthesis and the expression or activity of the limiting enzyme of the main biosynthetic pathway, cholesterol 7α-hydroxylase. Aim of this study was to correlate the levels of this metabolite with the rates of cholesterol 7α-hydroxylation in vivo, a direct measurement of bile acid synthesis, in hyperlipidemic patients. Design: Concentrations of 7α-hydroxy-4-cholesten-3-one were assayed by gas–liquid chromatography: mass spectrometry in plasma samples obtained in 18 patients with primary hyperlipoproteinemia who previously underwent determination of cholesterol 7α-hydroxylation rates in vivo by tritium release analysis. Both determinations were performed in basal conditions and after treatment with hypolipidemic drugs (the fibric acid derivatives gemfibrozil and bezafibrate, cholestyramine alone or associated with simvastatin). Results: Changes in plasma 7α-hydroxy-4-cholesten-3-one profile closely reflected in vivo cholesterol 7α-hydroxylation rates during treatment with fibrates, cholestyramine and cholestyramine plus simvastatin. When plotting determinations from all studies (n =40), a very strict correlation was disclosed between plasma 7α-hydroxy-4-cholesten-3-one and cholesterol 7α-hydroxylation rates (r =0.81, P <0.001). Conclusions: Plasma 7α-hydroxy-4-cholesten-3-one closely mirrors measurements of cholesterol 7α-hydroxylation rates in vivo in hyperlipidemic subjects and therefore stands as a reliable marker of global bile acid synthesis. In view of the correlation observed, these data may help to interpret changes of plasma levels of this metabolite in terms of cholesterol balance quantification. [Copyright &y& Elsevier]

• A rapid and reliable method for the analysis of 13 hypolipidemic drugs in fingerprints was developed. • UPLC-Q-TRAP/MS was applied to the detection and quantitation of these drugs. • The EPI mass spectrums of 13 hypolipidemic drugs were established. • Hypolipidemic drugs were proved to be excreted through sweat and/or sebaceous glands of the skin. An ultra-performance liquid chromatography tandem triple quadrupole compound linear ion trap mass spectrometry (UPLC-Q-TRAP/MS) method was developed and validated for the detection of hypolipidemic drugs in fingerprints. 13 hypolipidemic drugs were well separated by the gradient elution of 0.01% formic acid in water and methanol at a flow rate of 0.4 mL/min within 11 min. The analytes were detected in positive (ESI+) and negative (ESI-) modes and scanned using scheduled multiple reaction monitoring-information dependent acquisition-enhanced product ion (SMRM-IDA-EPI) for best selectivity and sensitivity. The calibration curves showed good linearity in the range of 0.050–50.000 ng/patch with coefficients (r2) higher than 0.9904 for all analytes. Meantime, the LODs and LLOQs were in ranges of 0.001–0.034 and 0.003–0.050 ng/patch. The accuracies, intra-day and inter-day precision ranged from −13.3 to 0.3%, 1.1–10.4% and 3.7–14.5%, respectively. The recoveries ranged from 79.9 to 114.8%, while the absolute and relative matrix effects were in the range of 83.0–107.2% and 2.2–9.7%. By comparing the non-spiked fingerprints from healthy volunteers with the fingerprints obtained from patients, demonstrated that the method was competent for determination and quantitation of hypolipidemic drugs in fingerprints. [ABSTRACT FROM AUTHOR]