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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

Total cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed control or high-cholesterol diets starting at the 5th dpf and continued for 14 days. Total cholesterol levels are expressed in μg cholesterol per mg protein of larvae lysate. Mean ± SEM from 6 independent experiments; 15–20 larvae were pooled for each experimental data point in each individual experiment. P < 0.005.
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fig1: Total cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed control or high-cholesterol diets starting at the 5th dpf and continued for 14 days. Total cholesterol levels are expressed in μg cholesterol per mg protein of larvae lysate. Mean ± SEM from 6 independent experiments; 15–20 larvae were pooled for each experimental data point in each individual experiment. P < 0.005.

Mentions: We have previously reported that plasma cholesterol levels in adult zebrafish rise from 200 to 800 mg/dL following 12 weeks of HCD feeding. Zebrafish larvae are too small to draw blood. Thus, we measured cholesterol levels in body fluids isolated from the larvae from which abdomens were removed and remaining bodies were gently homogenized. The homogenates were centrifuged to pellet tissue debris, and supernatants were used to extract total lipid and measure cholesterol using a gas chromatography method. A 2-week HCD feeding resulted in a 2.5-fold increase in cholesterol levels in zebrafish larvae (Figure 1). These results suggest that the experimental conditions used in experiments with zebrafish larvae reported in our earlier work [1, 5, 6] lead to significant elevations in cholesterol levels in larvae body fluids, comparable with hypercholesterolemia reported for adult zebrafish fed a HCD [1].


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

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

Total cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed control or high-cholesterol diets starting at the 5th dpf and continued for 14 days. Total cholesterol levels are expressed in μg cholesterol per mg protein of larvae lysate. Mean ± SEM from 6 independent experiments; 15–20 larvae were pooled for each experimental data point in each individual experiment. P < 0.005.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Total cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed control or high-cholesterol diets starting at the 5th dpf and continued for 14 days. Total cholesterol levels are expressed in μg cholesterol per mg protein of larvae lysate. Mean ± SEM from 6 independent experiments; 15–20 larvae were pooled for each experimental data point in each individual experiment. P < 0.005.
Mentions: We have previously reported that plasma cholesterol levels in adult zebrafish rise from 200 to 800 mg/dL following 12 weeks of HCD feeding. Zebrafish larvae are too small to draw blood. Thus, we measured cholesterol levels in body fluids isolated from the larvae from which abdomens were removed and remaining bodies were gently homogenized. The homogenates were centrifuged to pellet tissue debris, and supernatants were used to extract total lipid and measure cholesterol using a gas chromatography method. A 2-week HCD feeding resulted in a 2.5-fold increase in cholesterol levels in zebrafish larvae (Figure 1). These results suggest that the experimental conditions used in experiments with zebrafish larvae reported in our earlier work [1, 5, 6] lead to significant elevations in cholesterol levels in larvae body fluids, comparable with hypercholesterolemia reported for adult zebrafish fed a HCD [1].

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