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

被引：68

作者：

Tadin-Strapps, Marija ^{[1
]}

Peterson, Laurence B. ^{[2
]}

Cumiskey, Anne-Marie ^{[2
]}

Rosa, Raymond L. ^{[2
]}

Mendoza, Vivienne Halili ^{[2
]}

Castro-Perez, Jose ^{[2
]}

Puig, Oscar ^{[3
]}

Zhang, Liwen ^{[2
]}

Strapps, Walter R. ^{[1
]}

Yendluri, Satyasri ^{[1
]}

Andrews, Lori ^{[1
]}

Pickering, Victoria ^{[1
]}

Rice, Julie ^{[1
]}

Luo, Lily ^{[1
]}

Chen, Zhu ^{[2
]}

Tep, Samnang ^{[1
]}

Ason, Brandon ^{[1
]}

Somers, Elizabeth Polizzi ^{[2
]}

Sachs, Alan B. ^{[1
]}

Bartz, Steven R. ^{[1
]}

Tian, Jenny ^{[2
]}

Chin, Jayne ^{[2
]}

Hubbard, Brian K. ^{[2
]}

Wong, Kenny K. ^{[2
]}

Mitnaul, Lyndon J. ^{[2
]}

机构：

[1] Sirna Therapeut Inc, San Francisco, CA USA

[2] Merck & Co Inc, Div Cardiovasc Dis, Rahway, NJ 07065 USA

[3] Merck & Co Inc, Guided Solut, Rahway, NJ 07065 USA

来源：

JOURNAL OF LIPID RESEARCH | 2011年 / 52卷 / 06期

关键词：

low density lipoprotein cholesterol; low density lipoprotein receptor; cholesteryl ester transfer protein; short-interfering RNA; APOLIPOPROTEIN-E; FAMILIAL HYPERCHOLESTEROLEMIA; AGGRAVATES ATHEROSCLEROSIS; DENSITY-LIPOPROTEIN; TRANSFER PROTEIN; MICE; GENE; RNAI; HYPOBETALIPOPROTEINEMIA; HYPERLIPOPROTEINEMIA;

D O I：

10.1194/jlr.M012872

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.-Tadin-Strapps, M., L. B. Peterson, A-M. Cumiskey, R. L. Rosa, V. H. Mendoza, J. Castro-Perez, O. Puig, L. Zhang, W. R. Strapps, S. Yendluri, L. Andrews, V. Pickering, J. Rice, L. Luo, Z. Chen, S. Tep, B. Ason, E. P. Somers, A. B. Sachs, S. R. Bartz, J. Tian, J. Chin, B. K. Hubbard, K. K. Wong, and L. J. Mitnaul. siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids. J. Lipid Res. 2011. 52: 1084-1097.

引用

页码：1084 / 1097

页数：14

共 38 条

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