Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol
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ABSTRACT:
PROVIDER: PRJNA885114 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21742569_1.fastq.gz | Fastqsanger.gz | |||
| SRR21742569_2.fastq.gz | Fastqsanger.gz | |||
| SRR21742570_1.fastq.gz | Fastqsanger.gz | |||
| SRR21742570_2.fastq.gz | Fastqsanger.gz | |||
| SRR21742571_1.fastq.gz | Fastqsanger.gz |
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Project description:SURF4 is a cargo receptor that has been implicated in the intracellular trafficking of PCSK9 and APOB - proteins involved in cholesterol transport and metabolism. We generated hepatic SURF4-deficient mice (Surf4(fl/fl) Alb-Cre+) to investigate the physiologic role of SURF4 in vivo
2022-09-30 | GSE214393 | GEO
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:The brain is the most cholesterol-rich organ in the body, most of which comes from in situ synthesis. Here we demonstrate that in insulin-deficient diabetic mice, there is a reduction in expression of the major transcriptional regulator of cholesterol metabolism, SREBP-2, and its downstream genes in the hypothalamus and other areas of the brain, leading to a reduction in brain cholesterol synthesis and synaptosomal cholesterol content. These changes are due, at least in part, to direct effects of insulin to regulate these genes in neurons and glial cells and can be corrected by intracerebroventricular injections of insulin. Knockdown of SREBP-2 in cultured neurons causes a decrease in markers of synapse formation and reduction of SREBP-2 in the hypothalamus of mice using shRNA results in increased feeding and weight gain. Thus, insulin and diabetes can alter brain cholesterol metabolism, and this may play an important role in the neurologic and metabolic dysfunction observed in diabetes and other disease states. Hypothalamus was compared between streptozotocin (STZ)-induced diabetic, ob/ob, and control mice, with 5-6 replicates per goup.
2014-10-03 | E-GEOD-62013 | biostudies-arrayexpress
Project description:Cholesterol is the precursor of all steroids, but how cholesterol flux is controlled in steroidogenic tissues is poorly understood. The cholesterol exporter ABCG1 is an essential component of the reverse cholesterol pathway and its systemic inactivation results in neutral lipid redistribution to macrophages. However, the function of ABCG1 in steroidogenic organs is not explored. To model this question, we inactivated the ortholog Abcg1 gene in the mouse adrenal cortex. Abcg1 disruption led to an adrenal-specific increase in transcripts involved in cholesterol uptake and de novo synthesis, and to an 80% increase in corticosterone production. Importantly, this phenotype was not recapitulated by inactivation of the cholesterol exporter Abca1. The absence of any change in lipid profile suggested that adrenal Abcg1 is not involved in cholesterol export to a clinically relevant extent.
2023-09-05 | GSE242081 | GEO
Project description:The brain is the most cholesterol-rich organ in the body, most of which comes from in situ synthesis. Here we demonstrate that in insulin-deficient diabetic mice, there is a reduction in expression of the major transcriptional regulator of cholesterol metabolism, SREBP-2, and its downstream genes in the hypothalamus and other areas of the brain, leading to a reduction in brain cholesterol synthesis and synaptosomal cholesterol content. These changes are due, at least in part, to direct effects of insulin to regulate these genes in neurons and glial cells and can be corrected by intracerebroventricular injections of insulin. Knockdown of SREBP-2 in cultured neurons causes a decrease in markers of synapse formation and reduction of SREBP-2 in the hypothalamus of mice using shRNA results in increased feeding and weight gain. Thus, insulin and diabetes can alter brain cholesterol metabolism, and this may play an important role in the neurologic and metabolic dysfunction observed in diabetes and other disease states.
2014-10-03 | GSE62013 | GEO
Project description:Purpose: Employ next generation sequencing (NGS) to study the transcriptomic response to prolonged reduction in the cholesterol level, with emphasis on autophagy-related genes. Methods: Mv1Lu cells were subjected (or not; control) to cholesterol depletion (16 h, with lovastatin and mevalonate in the presence of lipoprotein deficient serum (LPDS), resulting in 30% reduction in the level of free cholesterol). mRNA profiles were generated by deep sequencing, in triplicates, using Illumina NextSeq500. See methods and protocols for details regarding downstream bioinformatic analysis. Results: Using an optimized data analysis workflow sequencing data from lung samples and identified that cholesterol depletion resulted in 2844 and 2822 genes with significantly increased or reduced expression, respectively. The set of differentially expressed genes was significantly enriched with functional annotations relating to cholesterol metabolic regulation and autophagy. These results were correlated with the upregulation of autophagy in biochemical studies. Conclusions: Mild reduction in the cholesterol level leads to a highly significant increase in the expression of multiple autophagy-related genes. The autophagy genes whose expression was modified by cholesterol depletion were scattered onto multiple steps of the autophagy process, and suggested a mainly positive regulation of autophagy by statin treatment.
2021-11-03 | GSE179869 | GEO
Project description:HP1gamma/Cbx3 deficiency results in reduction of H3K27me3 in mouse neurosphere neuronal genes
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Project description:Maternal obesity raises the risk of high-cholesterol exposure for their offspring. Studies in cohorts and animal models report that maternal obesity could increase the risk of neurodevelopmental disorders (NDDs) in offspring including intellectual disabilities and autism spectrum disorders (ASD). However, whether exposure to high cholesterol is responsible for brain developmental defects, as well as its underlying mechanism, is still unclear. Here, we constructed a cholesterol exposure model utilizing hiPSC-derived cerebral organoids by exogenously adding cholesterol into the culture system. We preformed scRNA sequence analysis to explore the gene expression changes in brain organoids under additional cholesterol exposure.
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Project description:Presenilin (PS) proteins represent the catalytic subunits of γ-secretase, and play a critical role in the generation of the Amyloid β (Aβ) peptide and the pathogenesis of Alzheimer’s disease (AD). Indeed, mutations in presenilin 1 (PS1) or PS2 are a major cause of early onset familial Alzheimer’s disease (FAD). However, PS proteins also exert multiple functions beyond Aβ generation. In this study, we examine the individual roles of PS1 and PS2 in cellular cholesterol metabolism. Deletion of PS1 or PS2 in mouse models led to cholesterol accumulation in cerebral neurons. Cholesterol accumulation was also observed in lysosomes of embryonic fibroblasts from PS1-KO and PS2-KO mice, and associated with decreased expression of the Niemann-Pick type C1 (NPC1) protein involved in intracellular cholesterol transport at late endosome/lysosome. Mass spectrometry and complementary biochemical methods also revealed abnormal N-glycosylation of NPC1 and several other membrane proteins in PS1-KO and PS2-KO cells. Interestingly, pharmacological inhibition of N-glycosylation resulted in intracellular cholesterol accumulation prominently in lysosomes as well as decrease of NPC1 expression in wild-type MEFs, thereby resembling the changes in PS1-KO and PS2-KO MEFs. In turn, treatment of PS1-KO and PS2-KO MEFs with a chaperone inducer, Arimoclomol, attenuated decrease of NPC1 and rescued the lysosomal cholesterol accumulation. Additionally, the intracellular cholesterol accumulation in PS1-KO and PS2-KO MEFs was prevented by NPC1 overexpression. Collectively, these data indicate that PS/γ-secretase dysfunction results in an impairment of protein N-glycosylation, which eventually causes NPC1 decrease and intracellular cholesterol accumulation. 3'RNASeq of mouse embryonic fibroblasts with PS1- or PS2-deficiency compared with controls. Biological replicates
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Project description:Modeling maternal cholesterol exposure reveals a reduction of neural progenitor proliferation using human cerebral organoids
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