SiRNAs induced long-term liver ApoB mRNA knockdown significantly lowers serum cholesterol in a mouse model with human-like serum lipids

Increased serum apoB and associated low density lipoprotein cholesterol (LDL) levels are well correlated with an increased risk of coronary disease. Apo E-/- and 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 siRNAs formulated in lipid nanoparticles (LNPs). 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, dose dependent and shows lipid lowering effects for over three weeks. Although specific TGs were affected by ApoB 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.

Dataset features

Information

Specifications

Application:	Gene expression microarray analysis
Number of samples:	17
Release date:	Nov 22 2010
Last update date:	Jun 14 2012
Access:	Public
Diseases:	Coronary Artery Disease, Coronary Disease, Mucocutaneous Lymph Node Syndrome, Parkinson Disease, Secondary
Chemicals:	Cholesterol
Dataset link	siRNAs induced long-term liver ApoB mRNA knockdown significantly lowers serum cholesterol in a mouse model with human-like serum lipids

Experimental Protocol

Two oligoes specific for ApoB were used to knock down apoB expression in C57Bl6 or B6-Ldlr(tm1)Tg(APOA1-CETP) mice. Gene expression profiling was performed with Affymetrix Merck Custom Mouse 1.0 microarrays (GPL9734).

Repositories

GEO

GSE23088

ArrayExpress

E-GEOD-23088

BioProject

PRJNA131887

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Contact

Oscar Puig