Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE214393 | GEO | 2022/09/30
REPOSITORIES: GEO
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Project description:PCSK9 negatively regulates low-density lipoprotein receptor (LDLR) abundance on the cell surface, leading to decreased hepatic clearance of LDL particles and increased levels of plasma cholesterol. We previously identified SURF4 as a cargo receptor that facilitates PCSK9 secretion in HEK293T cells (Emmer et al., 2018). Here, we generated hepatic SURF4-deficient mice (Surf4fl/fl Alb-Cre+) to investigate the physiologic role of SURF4 in vivo. Surf4fl/fl Alb-Cre+ mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by ~60% in Surf4fl/fl Alb-Cre+ mice, with a corresponding ~50% increase in steady state LDLR protein abundance in the liver, consistent with SURF4 functioning as a cargo receptor for PCSK9. Surprisingly, these mice exhibited a marked reduction in plasma cholesterol and triglyceride levels out of proportion to the partial increase in hepatic LDLR abundance. Detailed characterization of lipoprotein metabolism in these mice instead revealed a severe defect in hepatic lipoprotein secretion, consistent with prior reports of SURF4 also promoting the secretion of apolipoprotein B (APOB). Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4fl/fl Alb-Cre+ mice. Acute depletion of hepatic SURF4 by CRISPR/Cas9 or liver-targeted siRNA in adult mice confirms these findings. Together, these data support the physiologic significance of SURF4 in the hepatic secretion of PCSK9 and APOB-containing lipoproteins and its potential as a therapeutic target in atherosclerotic cardiovascular diseases.
| S-EPMC9581532 | biostudies-literature
Project description:Microarray analysis of WT (Pten2fl/fl:Shp2fl/fl:Alb-Cre-), SKO (Shp2hep-/-, or Shp2fl/fl:Alb-Cre+), PKO (Ptenhep-/-, or Pten2fl/fl:Alb-Cre+) and DKO (Ptenfl/fl:Shp2fl/fl:Alb-Cre+) liver samples to gain global molecular insights how shp2 and pten is involved in liver tumorigenesis.
2016-12-13 | GSE74732 | GEO
Project description:DNA methylation in gene promoter regions is a conserved, innate epigenetic mechanism to control gene expression. Transient application of epigenetic editors designed to induce DNA methylation has been shown to silence genes in cultured cells and in mice. Here we report the development of a potent, efficacious, and specific human PCSK9-targeting epigenetic editor. A single administration of lipid nanoparticles encapsulating mRNA encoding the epigenetic editor which precisely targets the PCSK9 locus was sufficient to drive near-complete silencing in transgenic mice expressing human PCSK9. Silencing was durable for at least one year and was fully maintained following partial hepatectomy-induced liver regeneration. In addition, we showed reversibility of epigenetic editing in previously silenced mice upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus. Importantly, a single administration of the epigenetic editor robustly, potently, and durably decreased circulating PCSK9 (~90%) in cynomolgus monkeys with concomitant reduction in low-density lipoprotein cholesterol (~70%). These findings support the development of an epigenetic editor targeting PCSK9 for the treatment of hypercholesterolemia and demonstrate the broad therapeutic potential of precise, efficacious, durable, and reversible epigenetic editing in vivo
2025-02-05 | GSE282432 | GEO
Project description:DNA methylation in gene promoter regions is a conserved, innate epigenetic mechanism to control gene expression. Transient application of epigenetic editors designed to induce DNA methylation has been shown to silence genes in cultured cells and in mice. Here we report the development of a potent, efficacious, and specific human PCSK9-targeting epigenetic editor. A single administration of lipid nanoparticles encapsulating mRNA encoding the epigenetic editor which precisely targets the PCSK9 locus was sufficient to drive near-complete silencing in transgenic mice expressing human PCSK9. Silencing was durable for at least one year and was fully maintained following partial hepatectomy-induced liver regeneration. In addition, we showed reversibility of epigenetic editing in previously silenced mice upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus. Importantly, a single administration of the epigenetic editor robustly, potently, and durably decreased circulating PCSK9 (~90%) in cynomolgus monkeys with concomitant reduction in low-density lipoprotein cholesterol (~70%). These findings support the development of an epigenetic editor targeting PCSK9 for the treatment of hypercholesterolemia and demonstrate the broad therapeutic potential of precise, efficacious, durable, and reversible epigenetic editing in vivo
2025-02-05 | GSE282441 | GEO
Project description:DNA methylation in gene promoter regions is a conserved, innate epigenetic mechanism to control gene expression. Transient application of epigenetic editors designed to induce DNA methylation has been shown to silence genes in cultured cells and in mice. Here we report the development of a potent, efficacious, and specific human PCSK9-targeting epigenetic editor. A single administration of lipid nanoparticles encapsulating mRNA encoding the epigenetic editor which precisely targets the PCSK9 locus was sufficient to drive near-complete silencing in transgenic mice expressing human PCSK9. Silencing was durable for at least one year and was fully maintained following partial hepatectomy-induced liver regeneration. In addition, we showed reversibility of epigenetic editing in previously silenced mice upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus. Importantly, a single administration of the epigenetic editor robustly, potently, and durably decreased circulating PCSK9 (~90%) in cynomolgus monkeys with concomitant reduction in low-density lipoprotein cholesterol (~70%). These findings support the development of an epigenetic editor targeting PCSK9 for the treatment of hypercholesterolemia and demonstrate the broad therapeutic potential of precise, efficacious, durable, and reversible epigenetic editing in vivo
2025-02-05 | GSE282445 | GEO
Project description:DNA methylation in gene promoter regions is a conserved, innate epigenetic mechanism to control gene expression. Transient application of epigenetic editors designed to induce DNA methylation has been shown to silence genes in cultured cells and in mice. Here we report the development of a potent, efficacious, and specific human PCSK9-targeting epigenetic editor. A single administration of lipid nanoparticles encapsulating mRNA encoding the epigenetic editor which precisely targets the PCSK9 locus was sufficient to drive near-complete silencing in transgenic mice expressing human PCSK9. Silencing was durable for at least one year and was fully maintained following partial hepatectomy-induced liver regeneration. In addition, we showed reversibility of epigenetic editing in previously silenced mice upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus. Importantly, a single administration of the epigenetic editor robustly, potently, and durably decreased circulating PCSK9 (~90%) in cynomolgus monkeys with concomitant reduction in low-density lipoprotein cholesterol (~70%). These findings support the development of an epigenetic editor targeting PCSK9 for the treatment of hypercholesterolemia and demonstrate the broad therapeutic potential of precise, efficacious, durable, and reversible epigenetic editing in vivo
2025-02-05 | GSE282436 | GEO
Project description:DNA methylation in gene promoter regions is a conserved, innate epigenetic mechanism to control gene expression. Transient application of epigenetic editors designed to induce DNA methylation has been shown to silence genes in cultured cells and in mice. Here we report the development of a potent, efficacious, and specific human PCSK9-targeting epigenetic editor. A single administration of lipid nanoparticles encapsulating mRNA encoding the epigenetic editor which precisely targets the PCSK9 locus was sufficient to drive near-complete silencing in transgenic mice expressing human PCSK9. Silencing was durable for at least one year and was fully maintained following partial hepatectomy-induced liver regeneration. In addition, we showed reversibility of epigenetic editing in previously silenced mice upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus. Importantly, a single administration of the epigenetic editor robustly, potently, and durably decreased circulating PCSK9 (~90%) in cynomolgus monkeys with concomitant reduction in low-density lipoprotein cholesterol (~70%). These findings support the development of an epigenetic editor targeting PCSK9 for the treatment of hypercholesterolemia and demonstrate the broad therapeutic potential of precise, efficacious, durable, and reversible epigenetic editing in vivo
2025-02-05 | GSE282521 | GEO
Project description:Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol
| PRJNA885114 | ENA
Project description:To identify HGF/Met regulated genes, we performed expression microarray analysis after inducible activation of Met receptor in primary cultures of hepatocytes established from wild-type control (Alb-Cre +/-) and Met conditional knockout mice (Alb-Cre +/-; Met Fl/Fl). Keywords: time series design
2006-10-02 | GSE4451 | GEO
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