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 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.
Clifton
Justin D
JD
Department Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
Lucumi
Edinson
E
Myers
Michael C
MC
Napper
Andrew
A
Hama
Kotaro
K
Farber
Steven A
SA
Smith
Amos B
AB
Huryn
Donna M
DM
Diamond
Scott L
SL
Pack
Michael
M
D000042:Absorption / Q000187:drug effects; D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004705:Endocytosis / Q000187:drug effects; D000069438:Ezetimibe; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D005240:Feasibility Studies; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D015027:Zebrafish / Q000378:metabolism*
D001384:Azetidines; D004041:Dietary Fats; D005227:Fatty Acids; D005456:Fluorescent Dyes; D010743:Phospholipids; D054852:Small Molecule Libraries; D002784:Cholesterol; D000069438:Ezetimibe
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