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21398511
siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids.

J Lipid Res, 2011/6;52(6):1084-1097.

Tadin-Strapps M[1], Peterson LB[2], Cumiskey AM[2], Rosa RL[2], Mendoza VH[2], Castro-Perez J[2], Puig O[3], Zhang L[2], Strapps WR[4], Yendluri S[4], Andrews L[4], Pickering V[4], Rice J[4], Luo L[4], Chen Z[2], Tep S[4], Ason B[4], Somers EP[2], Sachs AB[4], Bartz SR[4], Tian J[2], Chin J[2], Hubbard BK[2], Wong KK[2], Mitnaul LJ[2]

Affiliations

PMID: 21398511DOI: 10.1194/jlr.M012872

Impact factor: 6.676

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.
MeSH terms
Animals; Apolipoproteins B; Apolipoproteins E; Atherosclerosis; Cell Line, Tumor; Cholesterol Ester Transfer Proteins; Cholesterol, LDL; Disease Models, Animal; Founder Effect; Gene Expression Profiling; Gene Knockdown Techniques; Hemizygote; Humans; Lipid Metabolism; Liposomes; Liver; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nanoparticles; RNA, Messenger; RNA, Small Interfering; Receptors, LDL; Triglycerides
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