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Ezetimibe and simvastatin reduce cholesterol levels in zebrafish larvae fed a high-cholesterol diet.

Baek JS, Fang L, Li AC, Miller YI - Cholesterol (2012)

Bottom Line: We found that ezetimibe was well tolerated by zebrafish and effectively reduced cholesterol levels in HCD-fed larvae.Combination of low doses of ezetimibe and simvastatin had an additive effect in reducing cholesterol levels in zebrafish.These results suggest that ezetimibe exerts in zebrafish a therapeutic effect similar to that in humans and that the hypercholesterolemic zebrafish can be used as a low-cost and informative model for testing new drug candidates and for investigating mechanisms of action for existing drugs targeting dyslipidemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

ABSTRACT
Cholesterol-fed zebrafish is an emerging animal model to study metabolic, oxidative, and inflammatory vascular processes relevant to pathogenesis of human atherosclerosis. Zebrafish fed a high-cholesterol diet (HCD) develop hypercholesterolemia and are characterized by profound lipoprotein oxidation and vascular lipid accumulation. Using optically translucent zebrafish larvae has the advantage of monitoring vascular pathology and assessing the efficacy of drug candidates in live animals. Thus, we investigated whether simvastatin and ezetimibe, the principal drugs used in management of hypercholesterolemia in humans, would also reduce cholesterol levels in HCD-fed zebrafish larvae. We found that ezetimibe was well tolerated by zebrafish and effectively reduced cholesterol levels in HCD-fed larvae. In contrast, simvastatin added to water was poorly tolerated by zebrafish larvae and, when added to food, had little effect on cholesterol levels in HCD-fed larvae. Combination of low doses of ezetimibe and simvastatin had an additive effect in reducing cholesterol levels in zebrafish. These results suggest that ezetimibe exerts in zebrafish a therapeutic effect similar to that in humans and that the hypercholesterolemic zebrafish can be used as a low-cost and informative model for testing new drug candidates and for investigating mechanisms of action for existing drugs targeting dyslipidemia.

No MeSH data available.


Related in: MedlinePlus

Effect of simvastatin on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD with simvastatin mixed into zebrafish food at indicated quantities (μg simvastatin per gram food) for 14 days. Total cholesterol was measured in lipid extracts from larvae homogenates. Values of total cholesterol per larva were normalized to the values in the group that received HCD only (second column). Homogenates of 20 animals were pooled together for each data point in each individual experiment. Experiments with 0, 10, and 50 μg/g simvastatin were repeated twice, and average values from these two experiments are presented in the graph.
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fig2: Effect of simvastatin on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD with simvastatin mixed into zebrafish food at indicated quantities (μg simvastatin per gram food) for 14 days. Total cholesterol was measured in lipid extracts from larvae homogenates. Values of total cholesterol per larva were normalized to the values in the group that received HCD only (second column). Homogenates of 20 animals were pooled together for each data point in each individual experiment. Experiments with 0, 10, and 50 μg/g simvastatin were repeated twice, and average values from these two experiments are presented in the graph.

Mentions: To study the effect of simvastatin, we initially added it directly to water, as it has been reported in short-term studies [9]. However, we found that a prolonged exposure to simvastatin in water was toxic to zebrafish larvae. Varying the doses of simvastatin and the larval age at the beginning of treatment did not help improve zebrafish survival. Next, we mixed simvastatin into fish food at doses ranging from 0.1 to 50 μg per gram of food (μg/g). As estimated in Methods, a dose of, for example, 10 μg/g simvastatin administered with zebrafish food is roughly an equivalent of a 50 mg simvastatin dose administered to human patients. As shown in Figure 2, these doses of simvastatin were less effective than expected from short-term studies, with no significant difference between the group that received HCD alone and the group that received HCD with higher doses of simvastatin (P = 0.11, n = 4 for the combined 10 and 50 μg/g simvastatin group). As pharmacokinetics of simvastatin administered with food to zebrafish larvae has not been explored, these negative results could be due to a low effective dose of simvastatin. However, a higher dose is problematic given the toxicity of simvastatin added to water.


Ezetimibe and simvastatin reduce cholesterol levels in zebrafish larvae fed a high-cholesterol diet.

Baek JS, Fang L, Li AC, Miller YI - Cholesterol (2012)

Effect of simvastatin on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD with simvastatin mixed into zebrafish food at indicated quantities (μg simvastatin per gram food) for 14 days. Total cholesterol was measured in lipid extracts from larvae homogenates. Values of total cholesterol per larva were normalized to the values in the group that received HCD only (second column). Homogenates of 20 animals were pooled together for each data point in each individual experiment. Experiments with 0, 10, and 50 μg/g simvastatin were repeated twice, and average values from these two experiments are presented in the graph.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369394&req=5

fig2: Effect of simvastatin on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD with simvastatin mixed into zebrafish food at indicated quantities (μg simvastatin per gram food) for 14 days. Total cholesterol was measured in lipid extracts from larvae homogenates. Values of total cholesterol per larva were normalized to the values in the group that received HCD only (second column). Homogenates of 20 animals were pooled together for each data point in each individual experiment. Experiments with 0, 10, and 50 μg/g simvastatin were repeated twice, and average values from these two experiments are presented in the graph.
Mentions: To study the effect of simvastatin, we initially added it directly to water, as it has been reported in short-term studies [9]. However, we found that a prolonged exposure to simvastatin in water was toxic to zebrafish larvae. Varying the doses of simvastatin and the larval age at the beginning of treatment did not help improve zebrafish survival. Next, we mixed simvastatin into fish food at doses ranging from 0.1 to 50 μg per gram of food (μg/g). As estimated in Methods, a dose of, for example, 10 μg/g simvastatin administered with zebrafish food is roughly an equivalent of a 50 mg simvastatin dose administered to human patients. As shown in Figure 2, these doses of simvastatin were less effective than expected from short-term studies, with no significant difference between the group that received HCD alone and the group that received HCD with higher doses of simvastatin (P = 0.11, n = 4 for the combined 10 and 50 μg/g simvastatin group). As pharmacokinetics of simvastatin administered with food to zebrafish larvae has not been explored, these negative results could be due to a low effective dose of simvastatin. However, a higher dose is problematic given the toxicity of simvastatin added to water.

Bottom Line: We found that ezetimibe was well tolerated by zebrafish and effectively reduced cholesterol levels in HCD-fed larvae.Combination of low doses of ezetimibe and simvastatin had an additive effect in reducing cholesterol levels in zebrafish.These results suggest that ezetimibe exerts in zebrafish a therapeutic effect similar to that in humans and that the hypercholesterolemic zebrafish can be used as a low-cost and informative model for testing new drug candidates and for investigating mechanisms of action for existing drugs targeting dyslipidemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

ABSTRACT
Cholesterol-fed zebrafish is an emerging animal model to study metabolic, oxidative, and inflammatory vascular processes relevant to pathogenesis of human atherosclerosis. Zebrafish fed a high-cholesterol diet (HCD) develop hypercholesterolemia and are characterized by profound lipoprotein oxidation and vascular lipid accumulation. Using optically translucent zebrafish larvae has the advantage of monitoring vascular pathology and assessing the efficacy of drug candidates in live animals. Thus, we investigated whether simvastatin and ezetimibe, the principal drugs used in management of hypercholesterolemia in humans, would also reduce cholesterol levels in HCD-fed zebrafish larvae. We found that ezetimibe was well tolerated by zebrafish and effectively reduced cholesterol levels in HCD-fed larvae. In contrast, simvastatin added to water was poorly tolerated by zebrafish larvae and, when added to food, had little effect on cholesterol levels in HCD-fed larvae. Combination of low doses of ezetimibe and simvastatin had an additive effect in reducing cholesterol levels in zebrafish. These results suggest that ezetimibe exerts in zebrafish a therapeutic effect similar to that in humans and that the hypercholesterolemic zebrafish can be used as a low-cost and informative model for testing new drug candidates and for investigating mechanisms of action for existing drugs targeting dyslipidemia.

No MeSH data available.


Related in: MedlinePlus