title: Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: O'Hare
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: May E
authors.initials: ME
authors.lastname: Montasser
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Yen-Pei C
authors.initials: YP
authors.lastname: Chang
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Norann A
authors.initials: NA
authors.lastname: Zaghloul
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D001483:Base Sequence; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006529:Hepatomegaly / Q000150:complications; D006538:Heptanoic Acids / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000235:genetics; D010084:Oxidation-Reduction / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics*; D014680:Veins / Q000187:drug effects / Q000378:metabolism; D015027:Zebrafish
chemical_list: D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D060172:Morpholinos; D011758:Pyrroles; D011973:Receptors, LDL; D000069059:Atorvastatin
keywords: atherosclerosis; low density lipoprotein; low density lipoprotein cholesterol; low density lipoprotein receptor