PUBLICATION

Modeling hypercholesterolemia and vascular lipid accumulation in LDL receptor mutant zebrafish

Authors
Liu, C., Kim, Y.S., Kim, J., Pattison, J., Kamaid, A., Miller, Y.I.
ID
ZDB-PUB-171204-26
Date
2017
Source
Journal of Lipid Research   59(2): 391-399 (Journal)
Registered Authors
Kim, Jungsu, Liu, Chao, Miller, Yury
Keywords
Atherosclerosis, Cholesterol, LDL, LDL/Metabolism, Lipoproteins/Receptors, zebrafish
MeSH Terms
  • Animals
  • Atherosclerosis/genetics
  • Atherosclerosis/metabolism
  • Disease Models, Animal*
  • Hypercholesterolemia/metabolism*
  • Lipid Metabolism*
  • Lipids*
  • Mutation*
  • Receptors, LDL/deficiency
  • Receptors, LDL/genetics*
  • Receptors, LDL/metabolism
  • Zebrafish/genetics*
  • Zebrafish/metabolism*
PubMed
29187523 Full text @ J. Lipid Res.
Abstract
Elevated plasma LDL cholesterol is the dominant risk factor for the development of atherosclerosis and cardiovascular disease. Deficiency in the LDL receptor (LDLR) is a major cause of familial hypercholesterolemia in humans, and the LDLR knockout mouse is a major animal model of atherosclerosis. Here we report the generation and characterization of an ldlr mutant zebrafish as a new animal model to study hypercholesterolemia and vascular lipid accumulation, an early event in the development of human atherosclerosis. The ldlr mutant zebrafish were characterized by activated SREBP-2 pathway and developed moderate hypercholesterolemia when fed a normal diet. However, a short-term, 5-day feeding of ldlr mutant larvae with a high-cholesterol diet (HCD) resulted in exacerbated hypercholesterolemia and accumulation of vascular lipid deposits. Lomitapide, an inhibitor of apoB lipoprotein secretion, but not the antioxidant probucol, significantly reduced accumulation of vascular lipid deposits in HCD-fed ldlr mutant larvae. Furthermore, ldlr mutants were defective in hepatic clearance of lipopolysaccharides, resulting in reduced survival. Taken together, our data suggest that the ldlr knockout zebra-fish is a versatile model for studying the function of the LDL receptor, hypercholesterolemia, and related vascular pathology in the context of early atherosclerosis.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping