Limits...
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 combined simvastatin and ezetimibe treatments on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD for 14 days. Simvastatin and ezetimibe were administered as described in legends to Figures 1 and 2. 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 20–40 animals were pooled together for each data point in each individual experiment.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3369394&req=5

fig4: Effect of combined simvastatin and ezetimibe treatments on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD for 14 days. Simvastatin and ezetimibe were administered as described in legends to Figures 1 and 2. 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 20–40 animals were pooled together for each data point in each individual experiment.

Mentions: Next, we tested whether a combined treatment with ezetimibe (in water) and simvastatin (in food) would result in greater reductions in cholesterol levels in HCD-fed larvae. Concentrations of ezetimibe of 1 and 5 μM, combined with 10 or 50 μg/g simvastatin, reduced cholesterol to lower levels than individual treatments with ezetimibe or simvastatin (Figures 4(a), 4(b), and 4(c)), while combinations of higher concentrations of ezetimibe with simvastatin did not have any additive effect (Figures 4(d), 4(e), and 4(f)). Thus, even though simvastatin, under our experimental conditions, had little effect on cholesterol levels in zebrafish larvae, selected combinations of simvastatin with ezetimibe produced a greater effect in reducing cholesterol levels than each drug alone.


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 combined simvastatin and ezetimibe treatments on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD for 14 days. Simvastatin and ezetimibe were administered as described in legends to Figures 1 and 2. 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 20–40 animals were pooled together for each data point in each individual experiment.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Effect of combined simvastatin and ezetimibe treatments on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD for 14 days. Simvastatin and ezetimibe were administered as described in legends to Figures 1 and 2. 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 20–40 animals were pooled together for each data point in each individual experiment.
Mentions: Next, we tested whether a combined treatment with ezetimibe (in water) and simvastatin (in food) would result in greater reductions in cholesterol levels in HCD-fed larvae. Concentrations of ezetimibe of 1 and 5 μM, combined with 10 or 50 μg/g simvastatin, reduced cholesterol to lower levels than individual treatments with ezetimibe or simvastatin (Figures 4(a), 4(b), and 4(c)), while combinations of higher concentrations of ezetimibe with simvastatin did not have any additive effect (Figures 4(d), 4(e), and 4(f)). Thus, even though simvastatin, under our experimental conditions, had little effect on cholesterol levels in zebrafish larvae, selected combinations of simvastatin with ezetimibe produced a greater effect in reducing cholesterol levels than each drug alone.

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