Dataset Information

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

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.

SUBMITTER: Tadin-Strapps M

PROVIDER: S-EPMC3090230 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Tadin-Strapps Marija M Peterson Laurence B LB Cumiskey Anne-Marie AM Rosa Raymond L RL Mendoza Vivienne Halili VH Castro-Perez Jose J Puig Oscar O Zhang Liwen L Strapps Walter R WR Yendluri Satyasri S Andrews Lori L Pickering Victoria V Rice Julie J Luo Lily L Chen Zhu Z Tep Samnang S Ason Brandon B Somers Elizabeth Polizzi EP Sachs Alan B AB Bartz Steven R SR Tian Jenny J Chin Jayne J Hubbard Brian K BK Wong Kenny K KK Mitnaul Lyndon J LJ

Journal of lipid research 20110311 6

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 mi ...[more]

PMID: 21398511

Similar Datasets

Project description:Non-communicable diseases, including cardiovascular diseases (CVDs), are increasing in African populations. High serum low density lipoprotein cholesterol (LDL-cholesterol) levels are a known risk factor for CVDs in European populations, but the link remains poorly understood among Africans. This study investigated the associations between serum LDL-cholesterol levels and selected variants in the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and low density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes in some selected African populations. Nineteen SNPs were selected from publicly available African whole genome sequence data based on functional prediction and allele frequency. SNPs were genotyped in 1000 participants from the AWI-Gen, study selected from the extremes of LDL-cholesterol level distribution (500 with LDL-cholesterol>3.5 mmol/L and 500 with LDL-cholesterol<1.1 mmol/L). The minor alleles at five of the six associated SNPs were significantly associated (P<0.05) with lower LDL-cholesterol levels: LDLRAP1 rs12071264 (OR 0.56, 95% CI: 0.39-0.75, P = 2.73x10-4) and rs35910270 (OR 0.78, 95% CI: 0.64-0.94, P = 0.008); APOB rs6752026 (OR 0. 55, 95% CI: 0.41-0.72, P = 2.82x10-5); LDLR: rs72568855 (OR 0.47, 95% CI: 0.27-0.82, P = 0.008); and PCSK9 rs45613943 (OR = 0.72, 95% CI: 0.58-0.88, P = 0.001). The minor allele of the sixth variant was associated with higher LDL-cholesterol levels: APOB rs679899 (OR 1.41, 95% CI: 1.06-1.86, P = 0.016). A replication analysis in the Africa America Diabetes Mellitus (AADM) study found the PCSK9 variant to be significantly associated with low LDL-cholesterol levels (Beta = -0.10). Since Africans generally have lower LDL-cholesterol levels, these LDL-cholesterol associated variants may be involved in adaptation due to unique gene-environment interactions. In conclusion, using a limited number of potentially functional variants in four genes, we identified significant associations with lower LDL-cholesterol levels in sub-Saharan Africans.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets