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SiRNAs induced long-term liver ApoB mRNA knockdown significantly lowers serum cholesterol in a mouse model with human-like serum lipids

ABSTRACT: Increased serum apoB and associated low density lipoprotein cholesterol (LDL) levels are well correlated with an increased risk of coronary disease. Apo E-/- and 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 siRNAs formulated in lipid nanoparticles (LNPs). 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, dose dependent and shows lipid lowering effects for over three weeks. Although specific TGs were affected by ApoB 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE23088 | GEO | 2010/11/22

SECONDARY ACCESSION(S): PRJNA131887

REPOSITORIES: GEO

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siRNAs induced long-term liver ApoB mRNA knockdown significantly lowers serum cholesterol in a mouse model with human-like serum lipids

Project description:Increased serum apoB and associated low density lipoprotein cholesterol (LDL) levels are well correlated with an increased risk of coronary disease. Apo E-/- and 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 siRNAs formulated in lipid nanoparticles (LNPs). 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, dose dependent and shows lipid lowering effects for over three weeks. Although specific TGs were affected by ApoB 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. Two oligoes specific for ApoB were used to knock down apoB expression in C57Bl6 or B6-Ldlr(tm1)Tg(APOA1-CETP) mice. Gene expression profiling was performed with Affymetrix Merck Custom Mouse 1.0 microarrays (GPL9734).

2010-11-22 | E-GEOD-23088 | biostudies-arrayexpress

Evidence of mechanism how rs7575840 influences apolipoprotein B containing lipid particles

Project description:Objective: Recent genome-wide association studies (GWAS) identified a variant rs7575840 in the apolipoprotein B (APOB) gene region to be associated with LDL-C. However, the underlying functional mechanism of this variant that resides 6.5 kb upstream of APOB has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB containing lipid particles; for replication in a non-Caucasian Mexican population; and for underlying functional mechanism. Methods and Results Our data show that rs7575840 is associated with serum apoB levels (P=4.85x10-10) and apoB containing lipid particles, very small VLDL, IDL and LDL particles (P=2x10-5 - 9x10-7) in the Finnish METSIM study sample (n=7,710). Fine mapping of the APOB region using 43 SNPs replicated the association of rs7575840 with apoB in a Mexican study sample (n=2,666, P=3.33x10-05). Furthermore, our transcript analyses of adipose RNA samples from 175 Finnish METSIM subjects indicate that rs7575840 alters expression of APOB (P=1.13x10-10) and a regional non-coding RNA (BU630349) (P=7.86x10-6) in adipose tissue. Conclusions It has been difficult to convert GWAS associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB containing lipid particles as well as influences expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant SNP rs7575840 may affect serum apoB, LDL-C, and TC levels. 175 samples, no replicates

2011-08-31 | E-GEOD-27666 | biostudies-arrayexpress

Evidence of mechanism how rs7575840 influences apolipoprotein B containing lipid particles

2011-09-01 | GSE27666 | GEO

NHP Liver treated with Vehicle or LXR Ligand

Project description:The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR–IDOL axis are both tissue- and species-specific. In mice, LXR agonist induces Idol expression in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues but not in the liver and have minimal change in plasma LDL levels. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a strategy for LDL lowering in humans.

2014-12-31 | GSE61381 | GEO

Liver gene expression profiles of Tribbles-homolog1 (Trib1)/Ldl-receptor (Ldlr) double-knockout mice against Ldlr-knockout mice

Project description:Genetic variants at the TRIB1 (Tribbles-homolog 1) gene locus are strongly associated with plasma lipid traits and the risk of coronary artery disease in humans. In this study, we analyzed the consequences of Trib1-deficiency (Trib1-/-) on hepatic gene expression in mice on the atherosclerosis-susceptible LDL-receptor deficient (Ldlr-/-) background. Therefore, Trib1-/- mice were crossed onto the Ldlr-/- background to generate double knockout mice (Trib1-/-Ldlr-/-) and fed a semisynthetic, modified AIN76 diet (0.02% cholesterol, 4.3% fat). At 20 weeks of age, Trib1-/-Ldlr-/- mice and Trib1+/+Ldlr-/- control mice were sacrificed and liver tissue was snap frozen in liquid nitrogen and stored at -80°C until further processing. Total RNA was isolated from liver tissue (n=8 mice per genotype) and subjected to microarray gene expression analysis.

2023-03-15 | E-MTAB-12669 | biostudies-arrayexpress

Systematic transcriptome analysis of white tea based on microarray

Project description:Emerging in vivo and vitro data suggest that white tea extract (WTE) is capable of favourably modulating metabolic syndrome, especially by ameliorating abnormal lipid metabolism. Microarray-based gene expression profiling was performed in HepG2 cells to analyze the effects of WTE from a systematic perspective. Gene Ontology and pathway analysis revealed that WTE significantly affected pathways related to lipid metabolism. WTE significantly downregulated apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression and thereby reduced the production of very-low-density lipoprotein. In the meanwhile, WTE stimulated low-density lipoprotein-cholesterol (LDL-c) uptake through targeting low-density lipoprotein receptor (LDLR), as a consequence of the activation of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator-activated receptor δ (PPARδ). Furthermore, WTE significantly downregulated triglycerides synthetic genes and reduced intracellular triglycerides accumulation. Besides, we demonstrated that the tea catechins epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG) are abundant in WTE and contribute to the regulation of cholesterol metabolism related genes, including LDLR, MTTP and APOB. Our findings suggest white tea plays important roles in ameliorating abnormal lipid metabolism in vitro.

2018-12-07 | GSE123402 | GEO

Effect of Lactobacillus brevis 119-2 isolated from turnip “Tsuda kabu” on hepatic cholesterol level in cholesterol-administrated rat

Project description:In previous in vitro study, we reported potential mechanism of cholesterol-lowering effect of Lactobacillus brevis119-2 (119-2) isolated from turnip “Tsuda kabu” is due to incorporation of cholesterol into 119-2 cell. In this study, we analyzed serum cholesterol and hepatic gene expression of Sprague-Dawley (SD) rat fed diet containing cholesterol with or without 119-2 for 2 weeks, to evaluate the cholesterol-lowering effect of 119-2 in vivo. Serum cholesterol of SD rat fed diet with 119-2 significantly decreased compared to SD rat fed diet without 119-2, and both viable and dead 119-2 indicated the effect. The result of hepatic gene analysis using DNA microarray suggested that potential mechanism of the cholesterol-lowering effect of 119-2 in vivo is inhibiting the activity of 3-hydroxy-3-methylglutaryl-CoA reductase by Insig (insulin induced gene) that is endoplasmic reticulum membrane protein, and catabolizing cholesterol to bile acid by Cyp7a1 (cytochrome P450 a1) that is the rate-limiting enzyme in the synthesis of bile acid from cholesterol. In addition, we concluded feeding 119-2 decreased serum low density lipoprotein (LDL) cholesterol by overexpression of Ldlr (LDL receptor gene). On the other hand, feeding Lactobacillus acidophilus ATCC43121 (ATCC) increased high density lipoprotein (HDL) cholesterol by over expression of Abca1 (ATP binding cassette sub-family A member 1 gene) and Angplt3 (Angiopoietin-like 3). These results suggested that 119-2 decrease the risk of atherosclerosis by serum cholesterol-lowering effect and improving effect of fatty liver and the LH (LDL cholesterol / HDL cholesterol) ratio.

2013-04-24 | GSE41734 | GEO

The RNA-binding protein Hdlbp/Vigilin is increased in hepatic steatosis and regulates VLDL secretion through modulation of Apob mRNA translation

Project description:The liver exerts a wide range of essential functions including the synthesis of plasma proteins and the integration of glucose and lipid homeostasis. While the role of transcriptional networks in the tight regulation of these processes has been extensively studied in healthy and disease states, much less is known about post-transcriptional control of gene expression through RNA-binding proteins (RBP). Here, we report that the highly expressed and conserved RBP Hdlbp/Vigilin is upregulated in patients with non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and in livers of insulin resistant obese mice. Gain and loss of function studies revealed that Vigilin regulates VLDL secretion through the modulation of ApoB mRNA translation. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis in primary hepatocytes demonstrated that Vigilin predominantly binds to CU-rich regions in coding sequences of transcripts of further metabolically relevant secretory proteins such as Apob/apoliproteinB, Ahsg/fetuin-A, Apoc3/apolipoproteinC-III, Fn1/fibronectin, Orm1/orosomucoid and Serpina1/alpha-1-antitrypsin. While mRNA levels of these targets did not change, protein levels were substantially decreased upon knockdown of Vigilin. Hepatic long-term knockdown via GalNAc-conjugated siRNAs ameliorated elevated VLDL/LDL levels and the formation of atherosclerotic plaques in Ldlr–/– mice. These studies uncover a role for Vigilin as a key regulator of hepatic Apob translation and secretion through binding to its mRNA and demonstrate the therapeutic potential of inhibiting Vigilin for cardiovascular diseases.

2017-01-01 | GSE78084 | GEO

Apolipoprotein F in hyperlipidemia

Project description:Apolipoprotein F (ApoF) modulates lipoprotein metabolism by selectively inhibiting cholesteryl ester transfer protein (CETP) activity on LDL. This ApoF activity requires that it is bound to LDL. How hyperlipidemia alters total plasma ApoF and its binding to LDL are poorly understood. In this study, total ApoF and LDL-bound ApoF were quantified by ELISA. Plasma ApoF is increased 34% in hypercholesterolemic plasma. In hypertriglyceridemic plasma, ApoF was statistically unchanged. However, in donors with combined hypercholesterolemia and hypertriglyceridemia, the elevated triglyceride ameliorated the rise in ApoF caused by hypercholesterolemia alone. Compared to normolipidemic LDL, hypercholesterolemic LDL contained ~2-fold more ApoF per LDL particle, whereas ApoF bound to LDL in hypertriglyceridemia plasma was < 20% of control. To understand the basis for altered association of ApoF with hyperlipidemic LDL, the physiochemical properties of LDL were modified in vitro by CETP ± LCAT activities. The time-dependent change in LDL lipid composition, proteome, core and surface lipid packing, LDL surface charge, and LDL size caused by these factors were compared with the ApoF binding capacity of these LDL. Only LDL particle size correlated with ApoF binding capacity. This positive association between LDL size and ApoF content was confirmed in hyperlipidemic plasmas. Similarly, when in vitro-produced, enlarged LDL with elevated ApoF binding capacity were incubated with LPL to reduce their size, ApoF binding was reduced by 90%. Thus, plasma ApoF levels and the activation status of this ApoF are differentially altered by hypercholesterolemia and hypertriglyceridemia. LDL size is a key determinate of ApoF binding and activation.

2022-02-11 | PXD029713 | Pride

Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: a role for the LDL receptor and cholesterol metabolism in adult neural precursor cells (LDLR Knockdown)

Project description:In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis. We evaluated hippocampus-dependent behaviour and neurogenesis in adult C57BL/6JRj and LDLr-/- mice. Behavioural tests revealed that adult LDLr-/- mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr-/- mice, suggesting a potential direct impact of LDLr mutation on NPC. We thus investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown. Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.

2019-09-04 | GSE136797 | GEO

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