Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Asialogycoprotein receptor subunit ASGR1a deficiency leads to cholesterol malabsorption in zebrafish on a high-cholesterol diet

ABSTRACT: One of the major pathways to clear glycoproteins from circulation is via the liver-specific asialoglycoprotein receptor (ASGPR). Recently, loss of asialoglycoprotein receptor 1 (ASGR1), the major subunit of ASGPR in humans, was found to correlate with lower levels of plasma apolipoprotein B-containing lipoproteins (B-lps) and a profound reduction in cardiovascular disease risk. However, the cell and molecular biology underlying this effect was unclear. Given that rodents carry their cholesterol largely in HDL, we selected the zebrafish model to better understand the mechanism(s) of action of ASGR1. We first characterized all possible zebrafish ASGR1 orthologs to identify zebrafish ASGR1 (asgr1a) from a collection of lectin-binding proteins. We then generated two independent mutations in asgr1a using CRISPR/Cas9. Neither mutation altered larval, juvenile, or adult B-lp numbers or sizes. However, when challenged with a Western diet, asgr1a mutant zebrafish exhibited less hepatic steatosis and lower hepatic triglyceride levels compared to control animals. Asgr1a mutant animals also exhibited increased levels of fecal cholesterol, which we found was due to malabsorption after a meal and upregulation of liver proteins known to be involved in B-lp metabolism (e.g. MTP, APOA4). These data are consistent with the atheroprotective role of ASGR1 and reveal a previously unappreciated role for ASGR1 in modulating whole animal cholesterol flux.

ORGANISM(S): Danio rerio

PROVIDER: GSE330025 | GEO | 2026/05/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity.

Project description:Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity.

2024-01-29 | PXD046809 | Pride

ASGR1 Is a Promising Target for Lipid Reduction in Pigs with PON2 As Its Inhibitor

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.

2024-08-16 | GSE268910 | GEO

Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress

Project description:Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.

2023-11-26 | GSE232677 | GEO

Hepatocyte-like cells

Project description:Hepatocyte-like cells (HLCs) are derived from human pluripotent stem cells (hPSCs) in vitro, but differentiation protocols commonly give rise to a heterogeneous mixture of cells. This variability confounds the evaluation of in vitro functional assays performed using HLCs. We demonstrate the purification of a sub-population of functional HLCs differentiated from multiple hPSC lines using the hepatocyte surface marker Asialoglycoprotein Receptor 1 (ASGR1). We analyzed the expression profile of ASGR1-positive cells by microarray, and tested their ability to perform mature hepatocyte functions (albumin and urea secretion, cytochrome activity). By these measures, ASGR1-positive HLCs are enriched for the gene expression profile and functional characteristics of primary hepatocytes compared to unsorted HLCs.

2016-01-22 | GSE77086 | GEO

Hypomorphic ASGR1 Modulates Lipid Homeostasis via SREBPs Network

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.

2021-12-31 | GSE178370 | GEO

Microsomal triglyceride transfer protein restricts progesterone production in Leydig Cells by regulating SREBP2 activity [RNA-Seq]

Project description:Reduced serum testosterone or hypogonadism diminishes bone density, muscle mass, and sexual functions and increases obesity and CVD. Microsomal triglyceride transfer protein (MTP) is a lipid-transfer protein, primarily expressed in the liver and intestine, and is critical for apoB-containing lipoprotein assembly and secretion. MTP mRNA has been reported in the testis, but its function is unknown. Here, we report that MTP protein is present in the Leydig cells of human and mouse testes and plays a regulatory role in cholesterol metabolism and sex hormone production. Inhibition of the MTP activity by a specific inhibitor, knockdown, and gene ablation significantly increased progesterone secretion in mouse Leydig MA10 cells after stimulation with cyclic AMP. Molecular studies revealed that MTP enhanced the expression of genes in the uptake of lipoproteins, and in the synthesis and intracellular trafficking of cholesterol. Moreover, it enhanced the Lhcgr signaling as well as the expression of genes in the biosynthesis of progesterone. Transcriptome analysis confirmed increased expression of cholesterol and steroid biosynthesis pathways in MTP deficient clones. To understand how MTP deficiency increases expression of genes in cholesterol and steroid biosynthesis, we looked for changes in transcription factors. MTP deficiency enhanced the expression and activity of Srebp2. ATAC sequencing revealed enhanced binding of Srebp2 to the promoters of several enzymes in the biosynthesis of cholesterol and sex hormones. Furthermore, cholesterol and progesterone biosynthesis pathways were significantly attenuated after Srebp2 knockdown in MTP-deficient cells to the levels seen in wildtype cells. In short, these studies showed that MTP regulates cholesterol and steroid biosynthesis in Leydig cells by modulating the activity of Srebp2. Inhibition of testicular MTP might be useful to treat hypogonadism in some patients.

2026-04-13 | GSE305422 | GEO

Microsomal triglyceride transfer protein restricts progesterone production in Leydig Cells by regulating SREBP2 activity [ATAC-Seq]

2026-04-13 | GSE305421 | GEO

Hepatic processing of Z variant α-1-antitrypsin alters ERAD capacity to regulate cholesterol biosynthesis in a zebrafish model

Project description:Homozygosity for the Z allele of α1-antitrypsin (ZAAT) predisposes affected individuals to developing liver disease as the serpin misfolds and forms insoluble polymers that accumulate in the endoplasmic reticulum (ER) of hepatocytes, resulting in gain-of-function hepatotoxicity. This prevents secretion of ZAAT leading to serum insufficiency. A zebrafish model expressing human ZAAT in the liver shows no signs of hepatic accumulation despite displaying serum insufficiency, suggesting defect in ZAAT secretion occurs independently of its tendency to accumulate in hepatocytes. In this study, proteomic and transcriptomic analysis of the ZAAT-expressing zebrafish liver provided strong evidence of suppressed Srebp2-mediated cholesterol biosynthesis. qPCR confirms this observation in the human liver cell line stably expressing ZAAT. We proposed that the engagement of misfolded ZAAT by the ER-associated degradation (ERAD) system inhibits the turnover of Srebp2-repressing elements therefore hindering the activation of Srebp2. Protein quality control factors was manipulated to dissect the intracellular processing of ZAAT further mechanistically. Ablation of erlec1 resulted in a further suppression in the cholesterol biosynthesis pathway, confirming a role of this ER lectin in targeting misfolded ZAAT to ERAD. Deletion of the two ER mannosidase I homologs in zebrafish enhanced ZAAT secretion without inducing hepatic accumulation. Together, the present study provides novel insights into hepatic ZAAT processing and suggest potential therapeutic targets to improve ZAAT secretion and alleviate serum insufficiency in this form of α1-antitrypsin disease.

2023-03-10 | PXD036830 | Pride

Negative Feedback Regulation of Cholesterol Biosynthesis by MMAB

Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked with altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity, hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.

2021-09-10 | GSE183790 | GEO

Negative Feedback Regulation of Cholesterol Biosynthesis by MMAB

Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked to altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity and hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.

2021-06-01 | GSE169712 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data