학술논문
siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids[S]
Document Type
article
Author
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; Lyndon J. Mitnaul
Source
Journal of Lipid Research, Vol 52, Iss 6, Pp 1084-1097 (2011)
Subject
Language
English
ISSN
0022-2275
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.