Identification of novel inhibitors of dietary lipid absorption using zebrafish

Pharmacological inhibition of dietary lipid absorption induces favorable changes in serum lipoprotein levels in patients that are at risk for cardiovascular disease and is considered an adjuvant or alternative treatment with HMG-CoA reductase inhibitors (statins). Here we demonstrate the feasibility...

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Bibliographic Details
Published in:PloS one 2010-08, Vol.5 (8), p.e12386
Main Authors: Clifton, Justin D, Lucumi, Edinson, Myers, Michael C, Napper, Andrew, Hama, Kotaro, Farber, Steven A, Smith, 3rd, Amos B, Huryn, Donna M, Diamond, Scott L, Pack, Michael
Format: Article
Language:English
Subjects:
Absorption
Absorption - drug effects
Animals
Antilipemic agents
Azetidines - pharmacology
Biotechnology/Small Molecule Chemistry
Cardiovascular diseases
Care and treatment
Chemical compounds
Chemistry
Cholesterol
Cholesterol - analogs & derivatives
Cholesterol - metabolism
Danio rerio
Diabetes
Diet
Dietary Fats - metabolism
Disease susceptibility
Drug Evaluation, Preclinical
Embryology
Endocytosis - drug effects
Endoplasmic reticulum
Engineering
Ezetimibe
Fatty acids
Fatty Acids - chemistry
Fatty Acids - metabolism
Feasibility Studies
Fluorescence
Fluorescent Dyes - metabolism
Freshwater
Gallbladder
Health risks
HMG-CoA reductase inhibitors
Humans
Hydroxymethylglutaryl-CoA reductase
Inhibition
Inhibitors
Intestine
Larva - drug effects
Larva - metabolism
Larvae
Lipid Metabolism - drug effects
Lipids
Medicine
Metabolism
Metabolites
Pharmacology
Phospholipids - chemistry
Phospholipids - metabolism
Physiological aspects
Physiology/Cardiovascular Physiology and Circulation
Physiology/Gastroenterology and Hepatology
Rodents
Small Molecule Libraries - pharmacology
Statins
Target recognition
Zebrafish
Zebrafish - metabolism
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Summary:Pharmacological inhibition of dietary lipid absorption induces favorable changes in serum lipoprotein levels in patients that are at risk for cardiovascular disease and is considered an adjuvant or alternative treatment with HMG-CoA reductase inhibitors (statins). Here we demonstrate the feasibility of identifying novel inhibitors of intestinal lipid absorption using the zebrafish system. A pilot screen of an unbiased chemical library identified novel compounds that inhibited processing of fluorescent lipid analogues in live zebrafish larvae. Secondary assays identified those compounds suitable for testing in mammals and provided insight into mechanism of action, which for several compounds could be distinguished from ezetimibe, a drug used to inhibit cholesterol absorption in humans that broadly inhibited lipid absorption in zebrafish larvae. These findings support the utility of zebrafish screening assays to identify novel compounds that target complex physiological processes.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0012386