Hypomorphic ASGR1 Modulates Lipid Homeostasis via SREBPs Network
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA738702 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14851316_1.fastq.gz | Fastqsanger.gz | |||
| SRR14851316_2.fastq.gz | Fastqsanger.gz | |||
| SRR14851317_1.fastq.gz | Fastqsanger.gz | |||
| SRR14851317_2.fastq.gz | Fastqsanger.gz | |||
| SRR14851318_1.fastq.gz | Fastqsanger.gz |
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Project description:A population genetic study identified that the asialoglycoprotein receptor 1 (ASGR1) mutation carriers had significantly lower non-HDL-c levels and reduced risks of cardiovascular diseases. However, the mechanism behind this phenomenon remained unclear. Here, we established Asgr1 knockout mice that represented a plasma lipid profile with significantly lower non-HDL-c and triglyceride caused by decreased secretion and increased uptake of VLDL/LDL. These two phenotypes were linked with the decreased expression of microsomal triglyceride transfer protein (MTTP) and proprotein convertase subtilisin/kexin type 9 (PCSK9), two key target genes of the sterol regulatory element-binding proteins (SREBPs). Furthermore, there were less nSREBPs on account of more SREBPs being trapped in endoplasmic reticulum, which was caused by an increased expression of insulin-induced gene 1 (INSIG1), an anchor of SREBPs. Logically, two rescue experiments were conducted in ASGR1 deficient condition. Both INSIG1 knockdown and ASGR1 rescue independently reversed the ASGR1-mutated phenotypes, restoring the SREBP signaling manifested by improved APOB secretion and reduced LDL uptake. Our observation demonstrated a novel axis of ASGR1-INSIG1-SREBPs regulating lipid hemostasis, and hypomorphic manipulation of ASGR1 leads to significant reduction of lipid content via less nSREBPs. It provides multiple potential targets, including ASGR, for lipid-lowering drug development.
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Project description:Although the role of asialoglycoprotein receptor 1 (ASGR1) in lowering lipid levels is well established, recent studies indicate that ASGR1 inhibition can cause unexpected liver damage in pigs, raising a serious issue about whether ASGR1 can be a good target for treating ASCVD. Here, we utilized the CRISPR/Cas9 system to regenerate ASGR1-knockout pigs, who displayed decreased lipid profiles without observable liver damage, which were confirmed by the lower levels of serum ALT and AST, reduced expression of inflammation markers, and normal histological morphology. Also, we implemented immunoprecipitation combined with mass spectrometry (IP-MS) and discovered that Paraoxonase-2 (PON2) can interact with and significantly degrade ASGR1 in a dose-dependent manner. This degradation led to reduced lipid levels in mice, accompanied by little inflammation. Our study highlights the effectiveness and safety of degrading ASGR1 to reduce lipid levels in pigs and provides a potential inhibitor of ASGR1.
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Project description:Lipid composition can differ widely among organelles and even between leaflets of a membrane. Lipid homeostasis is critical because disequilibrium can have disease outcomes. Despite their importance, mechanisms maintaining lipid homeostasis remain poorly understood. Here, we establish a model system to study the global effects of lipid imbalance. Quantitative lipid profiling was integral to monitor changes to lipid composition and for system validation. Applying global transcriptional and proteomic analyses, a dramatically altered biochemical landscape was revealed from adaptive cells. The resulting composite regulation we term the ?membrane stress response? (MSR) confers compensation, not through restoration of lipid composition, but by remodeling the protein homeostasis network. To validate its physiological significance, we analyzed the unfolded protein response (UPR), one facet of the MSR and a key regulator of protein homeostasis. We demonstrate that the UPR maintains protein biogenesis, quality control, and membrane integrity?functions otherwise lethally compromised in lipid dysregulated cells. Genes expression from early log phase of CHO2, OPI3, and PAH1 knockout cell and untreated and DTT-treated WT cells. RNA was prepared from independent triplicate samples. Array sets performed and collected on different dates are as follows: Array 1, Day 1: WT_rep1 pah1_rep1 cho2_rep1 opi3_rep1 Array 2, Day 2: WT_rep2 WT_rep3 WT_Tm_rep1 WT_DTT_rep1 Array 3, Day 2: WT_DTT_rep2 WT_DTT_rep3 cho2_rep2 cho2_rep3 Array 4, Day 2: pah1_rep2 pah1_rep3 opi3_rep2 opi3_rep3
2012-09-25 | E-GEOD-39419 | biostudies-arrayexpress
Project description:A population genetic study identified that the asialoglycoprotein receptor 1 (ASGR1) mutation carriers had substantially lower non-HDL-cholesterol (non-HDL-c) levels and reduced risks of cardiovascular diseases. However, the mechanism behind this phenomenon remained unclear. Here, we established Asgr1-knockout mice that represented a plasma lipid profile with significantly lower non-HDL-c and triglyceride (TG) caused by decreased secretion and increased uptake of VLDL/LDL. These 2 phenotypes were linked with the decreased expression of microsomal triglyceride transfer protein and proprotein convertase subtilisin/kexin type 9, 2 key targeted genes of sterol regulatory element-binding proteins (SREBPs). Furthermore, there were fewer nuclear SREBPs (nSREBPs) on account of more SREBPs being trapped in endoplasmic reticulum, which was caused by an increased expression of insulin-induced gene 1 (INSIG1), an anchor of SREBPs. Overexpression and gene knockdown interventions, in different models, were conducted to rescue the ASGR1-deficient phenotypes, and we found that INSIG1 knockdown independently reversed the ASGR1-mutated phenotypes with increased serum total cholesterol, LDL-c, TG, and liver cholesterol content accompanied by restored SREBP signaling. ASGR1 rescue experiments reduced INSIG1 and restored the SREBP network defect as manifested by improved apolipoprotein B secretion and reduced LDL uptake. Our observation demonstrated that increased INSIG1 is a critical factor responsible for ASGR1 deficiency-associated lipid profile changes and nSREBP suppression. This finding of an ASGR1/INSIG1/SREBP axis regulating lipid hemostasis may provide multiple potential targets for lipid-lowering drug development.
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Project description:Lipid composition can differ widely among organelles and even between leaflets of a membrane. Lipid homeostasis is critical because disequilibrium can have disease outcomes. Despite their importance, mechanisms maintaining lipid homeostasis remain poorly understood. Here, we establish a model system to study the global effects of lipid imbalance. Quantitative lipid profiling was integral to monitor changes to lipid composition and for system validation. Applying global transcriptional and proteomic analyses, a dramatically altered biochemical landscape was revealed from adaptive cells. The resulting composite regulation we term the ?membrane stress response? (MSR) confers compensation, not through restoration of lipid composition, but by remodeling the protein homeostasis network. To validate its physiological significance, we analyzed the unfolded protein response (UPR), one facet of the MSR and a key regulator of protein homeostasis. We demonstrate that the UPR maintains protein biogenesis, quality control, and membrane integrity?functions otherwise lethally compromised in lipid dysregulated cells.
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