Hyperlipidemia and arterial
cholesterol accumulation are primary causes of cardiovascular events. Monogenic forms of
hyperlipidemia and recent genome-wide association studies indicate that genetics plays an important role. Zebrafish are a useful model for studying the
genetic susceptibility to
hyperlipidemia owing to conservation of many components of
lipoprotein metabolism, including those related to
LDL, ease of genetic manipulation, and in vivo observation of
lipid transport and
vascular calcification. We sought to develop a genetic model for lipid metabolism in zebrafish, capitalizing on one well-understood player in
LDL cholesterol (
LDL-c) transport, the
LDL receptor (ldlr), and an established in vivo model of
hypercholesterolemia. We report that
morpholinos targeted against the gene encoding ldlr effectively suppressed its expression in embryos during the first 8 days of development. The ldlr morphants exhibited increased
LDL-c levels that were exacerbated by feeding a high
cholesterol diet. Increased
LDL-c was ameliorated in morphants upon treatment with
atorvastatin. Furthermore, we observed significant vascular and liver
lipid accumulation, vascular leakage, and plaque oxidation in ldlr-deficient embryos. Finally, upon transcript analysis of several
cholesterol-regulating genes, we observed changes similar to those seen in mammalian systems, suggesting that
cholesterol regulation may be conserved in zebrafish. Taken together, these observations indicate conservation of ldlr function in zebrafish and demonstrate the utility of transient gene knockdown in embryos as a genetic model for
hyperlipidemia.