TY - JOUR
T1 - siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids
AU - Tadin-Strapps, Marija
AU - Peterson, Laurence B.
AU - Cumiskey, Anne Marie
AU - Rosa, Raymond L.
AU - Mendoza, Vivienne Halili
AU - Castro-Perez, Jose
AU - Puig, Oscar
AU - Zhang, Liwen
AU - Strapps, Walter R.
AU - Yendluri, Satyasri
AU - Andrews, Lori
AU - Pickering, Victoria
AU - Rice, Julie
AU - Luo, Lily
AU - Chen, Zhu
AU - Tep, Samnang
AU - Ason, Brandon
AU - Somers, Elizabeth Polizzi
AU - Sachs, Alan B.
AU - Bartz, Steven R.
AU - Tian, Jenny
AU - Chin, Jayne
AU - Hubbard, Brian K.
AU - Wong, Kenny K.
AU - Mitnaul, Lyndon J.
PY - 2011/6
Y1 - 2011/6
N2 - 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.
AB - 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.
KW - Cholesteryl ester transfer protein
KW - Low density lipoprotein cholesterol
KW - Low density lipoprotein receptor
KW - Short-interfering RNA
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U2 - 10.1194/jlr.M012872
DO - 10.1194/jlr.M012872
M3 - Article
C2 - 21398511
AN - SCOPUS:79956022523
SN - 0022-2275
VL - 52
SP - 1084
EP - 1097
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 6
ER -