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.
Highlights
Elevated plasma LDL cholesterol is the dominant risk factor for the development of atherosclerosis and cardiovascular disease
The ldlr mutant zebrafish developed in this study adds to the set of zebrafish models of lipid abnormalities and lipoprotein oxidation, which includes apoc2 mutant zebrafish that develop severe hypertriglyceridemia [13], loss and gain of function liver X receptor mutants [29, 30], and hsp70:IK17-EGFP zebrafish that serve as a reporter for oxidation-specific epitopes [20], among others
We have previously been able to achieve hypercholesterolemia in WT zebrafish by feeding larvae an highcholesterol diet (HCD) for 2 weeks, which resulted in accumulation of vascular lipid deposits [14]
Summary
Elevated plasma LDL cholesterol is the dominant risk factor for the development of atherosclerosis and cardiovascular disease. 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. A short-term, 5-day feeding of ldlr mutant larvae with a highcholesterol diet (HCD) resulted in exacerbated hypercholesterolemia and accumulation of vascular lipid deposits. Examples of such non-LDLR pathway therapies include lomitapide, an inhibitor of microsomal triglyceride transfer protein (MTP), and mipomersen, an antisense oligonucleotide targeting apoB mRNA These two drugs inhibit assembly and secretion of hepatic and intestinal lipoproteins [9]. Ldlr / mice [11, 12] have been instrumental in understanding mechanisms of atherosclerosis, Abbreviations: dpf, days postfertilization; FH, familial hypercholesterolemia; HCD, high-cholesterol diet; HMGCR, HMG-CoA reductase; LDL-C, LDL cholesterol; LDLR, LDL receptor; LPS, lipopolysaccharide; ORO, Oil Red O; TG, triglyceride
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