Abstract
Increased serum apolipoprotein (apo)B and associated LDL levels are well-correlated with an increased risk of coronary disease. ApoE⁻/⁻ and low density lipoprotein receptor (LDLr)⁻/⁻ mice have been extensively used for studies of coronary atherosclerosis. These animals show atherosclerotic lesions similar to those in humans, but their serum lipids are low in apoB-containing LDL particles. We describe the development of a new mouse model with a human-like lipid profile. Ldlr CETP⁺/⁻ hemizygous mice carry a single copy of the human CETP transgene and a single copy of a LDL receptor mutation. To evaluate the apoB pathways in this mouse model, we used novel short-interfering RNAs (siRNA) formulated in lipid nanoparticles (LNP). ApoB siRNAs induced up to 95% reduction of liver ApoB mRNA and serum apoB protein, and a significant lowering of serum LDL in Ldlr CETP⁺/⁻ mice. ApoB targeting is specific and dose-dependent, and it shows lipid-lowering effects for over three weeks. Although specific triglycerides (TG) were affected by ApoB mRNA knockdown (KD) and the total plasma lipid levels were decreased by 70%, the overall lipid distribution did not change. Results presented here demonstrate a new mouse model for investigating additional targets within the ApoB pathways using the siRNA modality.
Highlights
Increased serum apolipoproteinB and associated low density lipoprotein cholesterol (LDL) levels are well-correlated with an increased risk of coronary disease
We demonstrated that lipid nanoparticles (LNP)-formulated short-interfering RNAs (siRNA) can be successfully used in Ldlr+/– cholesteryl ester transfer protein (CETP)+/– hemizygous mice to achieve hepatic ApoB mRNA knockdown and that this reduction in ApoB mRNA levels results in significant reductions in serum ApoB protein, changes in genes in the lipid and fatty acid pathways, significant and prolonged reductions in serum total cholesterol, triglycerides, and LDL levels, as well as correlative hepatic steatosis
These mice were genetically engineered to contain one copy of human cholesteryl ester transfer protein (CETP+/–), driven by the human ApoA1 promoter, and they are hemizygous for the LDL receptor mutation (Ldlr+/–) as described in Materials and Methods
Summary
Increased serum apolipoprotein (apo)B and associated LDL levels are well-correlated with an increased risk of coronary disease. Since wild-type mice have very high anti-atherogenic high density lipoprotein (HDL) and low pro-atherogenic LDL lipoprotein levels, genetic manipulations have been necessary for development of mouse models of coronary atherosclerosis. Development of these animal models started with the discovery of human mutations in individuals with lipoprotein disorders. LDLr–/–, Apo E–/–, and ApoE3-Leiden transgenic mice have been widely used as mouse models of atherosclerosis [6,7,8,9] These animals show a range of changes in serum lipids in response to different diets and exhibit atherosclerotic lesions very similar to the lesions found in humans. These animals have serum lipid profiles that are very different from those of normal healthy humans that make them less than optimal for use in studies of lipid homeostasis
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