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 ezetimibe on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD for 14 days. Ezetimibe was added at indicated concentrations directly to fish tank water, and the water was changed every day. 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, 1, and 5 μM ezetimibe were repeated three times, and average values from these three experiments are presented in the graph.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Effect of ezetimibe on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD for 14 days. Ezetimibe was added at indicated concentrations directly to fish tank water, and the water was changed every day. 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, 1, and 5 μM ezetimibe were repeated three times, and average values from these three experiments are presented in the graph.

Mentions: In contrast to simvastatin, adding ezetimibe to water did not affect survival of larvae, their swimming pattern nor apparent food intake. Based on the range of doses of ezetimibe that has been reported to inhibit intestinal cholesterol absorption in zebrafish larvae [8], we tested 0.1–50 μM ezetimibe added to water. We found that ezetimibe was very effective in reducing cholesterol levels in HCD-fed larvae (Figure 3). Already at the concentration of 1 μM, ezetimibe reduced cholesterol to the levels observed in larvae fed control diet (P = 0.39 for the hypothesis that means of “control” and “HCD + ezetimibe” are different, n = 3).


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 ezetimibe on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD for 14 days. Ezetimibe was added at indicated concentrations directly to fish tank water, and the water was changed every day. 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, 1, and 5 μM ezetimibe were repeated three times, and average values from these three experiments are presented in the graph.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Effect of ezetimibe on cholesterol levels in HCD-fed zebrafish larvae. Zebrafish larvae were fed a HCD for 14 days. Ezetimibe was added at indicated concentrations directly to fish tank water, and the water was changed every day. 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, 1, and 5 μM ezetimibe were repeated three times, and average values from these three experiments are presented in the graph.
Mentions: In contrast to simvastatin, adding ezetimibe to water did not affect survival of larvae, their swimming pattern nor apparent food intake. Based on the range of doses of ezetimibe that has been reported to inhibit intestinal cholesterol absorption in zebrafish larvae [8], we tested 0.1–50 μM ezetimibe added to water. We found that ezetimibe was very effective in reducing cholesterol levels in HCD-fed larvae (Figure 3). Already at the concentration of 1 μM, ezetimibe reduced cholesterol to the levels observed in larvae fed control diet (P = 0.39 for the hypothesis that means of “control” and “HCD + ezetimibe” are different, n = 3).

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