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siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids[S]

By Marija Tadin-Strapps, Laurence B. Peterson, Anne-Marie Cumiskey, Raymond L. Rosa, Vivienne Halili Mendoza, Jose Castro-Perez, Oscar Puig, Liwen Zhang, Walter R. Strapps, Satyasri Yendluri, Lori Andrews, Victoria Pickering, Julie Rice, Lily Luo, Zhu Chen, Samnang Tep, Brandon Ason, Elizabeth Polizzi Somers, Alan B. Sachs, Steven R. Bartz, Jenny Tian, Jayne Chin, Brian K. Hubbard, Kenny K. Wong and Lyndon J. Mitnaul

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

Topics: Research Articles
Publisher: The American Society for Biochemistry and Molecular Biology
OAI identifier: oai:pubmedcentral.nih.gov:3090230
Provided by: PubMed Central
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