Accumulation of mutant Z α1-Antitrypsin impairs intestinal function in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE291017 | GEO | 2026/06/29
REPOSITORIES: GEO
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Project description:Cargo receptor-assisted endoplasmic reticulum export of pathogenic α1-antitrypsin polymers
| PRJNA665693 | ENA
Project description:Alpha 1-Antitrypsin Deficiency (AATD) is a rare genetic disorder caused by mutations in the SERPINA1 gene, which encodes the Alpha 1-Antitrypsin (AAT) protein. Individuals carrying pathogenic SERPINA1 variants are predisposed to lung and liver damage. The most common AATD-associated SERPINA1 alleles are the S and Z alleles, though additional variants have been identified. This case report describes the discovery of a new SERPINA1 variant detected in two cities in southeastern France. This variant, named PiZmarseille, results from in cis combination of the PiZ allele and a rare variant known as PiZbristol. PiZmarseille has been associated with early-onset liver disease in childhood. To further investigate this new variant, we performed its molecular characterization, revealing that PiZmarseille shares the pathogenic properties of both the PiZ and PiZbristol variants. These properties include its retention in the endoplasmic reticulum as aggregates and its degradation through the autophagy and proteasome pathways. Additionally, we conducted proteomic profiling to explore the association of this mutant with liver disease. Our analysis revealed that the neutrophil degranulation pathway is particularly deregulated in PiZmarseille liver samples. Furthermore, when compared to other AAT genotypes, the proteomic profile of PiZmarseille most closely resembles that of the PiZ variant, rather than other SERPINA1 variants.
2025-12-08 | PXD060960 | Pride
Project description:To investigate the role of CHOP in the pathogenesis of liver disease due to Z alpha-1 antitrypsin in juvenile and older mice, we performed Quant-seq experiments at 6 and 36 weeks of age in wild type, PiZ and PiZ/Chop-/- mouse livers
2020-08-13 | GSE141593 | GEO
Project description:Individuals expressing alpha-1-antitrypsin mutant Z protein accumulate misfolded, mutant protein in the liver and are at risk for liver diseases including cirrhosis and hepatocellular carcinoma. Transgenic PiZ mice, a model for this liver disease, display similar pathologies to humans, including inflammation, increases in proliferation, autophagy and apoptosis, accumulation of globules and develop fibrosis and hepatocellular carcinoma with age. Microarrays were used to compare the gene expressions of PiZ mice to wild-type mice in order to identify the pathways that are altered in this disorder. Pooled samples from 4 mice, 3-4 months old were used for each of 4 categories. PiZ males, PiZ females, C57Bl/6 males, C57Bl/6 females
2012-11-08 | E-GEOD-36478 | biostudies-arrayexpress
Project description:Background: Angiopoietin-like 3 (ANGPTL3) is a hepatokine acting as negative regulator of hepatic and endothelial lipases. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 60% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels also correlates with liver fat accumulation. Methods: To further elucidate the biological activity of ANGPTL3 on lipid metabolism in the liver we performed a RNAseq analysis from human hepatoma Huh7 cells transfected with siRNA-ANGPTL3, siRNA-PCSK9 and double siRNA-ANGPTL3/PCSK9. Results: RNA-seq analysis detected 192 genes out of 13,945 transcripts differential ex-pressed in response to ANGPTL3-siRNA compared to scramble-siRNA controls. In cells transfected with PCSK9-siRNA, 88 genes were differentially expressed, while dual transfection with both ANGPTL3- and PCSK9-siRNA resulted in 219 differentially ex-pressed genes. When ANGPTL3 gene expression was silenced we observed a compensa-tory induction of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and pro-tein expression. Moreover, PCSK9 silencing increased ANGPTL3 mRNA expression. Bi-oinformatic analysis revealed that gene silencing of ANGPTL3 or both ANGPTL3/PCSK9 suppresses SERPINA1, gene encoding α1-antitrypsin, and lectin mannose-binding 1 ex-pression (LMAN1). These data were confirmed by western blot and qRT-PCR analysis. Conclusions: Our data identified two key genes SERPINA1 and LMAN1, involved in endoplasmic reticulum stress, lipid accumulation and liver damage, that are downregu-lated in response to gene silencing of ANGPTL3 in Huh7 hepatoma cell line.
2026-02-02 | GSE312289 | GEO
Project description:Gene silencing of ANGPTL3 suppresses α1-antitrypsin and lectin mannose-binding 1 expression in the hepatoma Huh7 cell line
| PRJNA1372774 | ENA
Project description:Background: Circulating polymers of alpha1-antitrypsin (α1AT) are chemo-attractant for neutrophils and contribute to inflammation in pulmonary, vascular and adipose tissues. Cellular factors affecting the intracellular itinerary of mutant polymerogenic α1AT remain obscure. Methods: Here, we report on an unbiased genome-wide CRISPR/Cas9 screen for regulators of trafficking of the polymerogenic α1AT-H334D variant. Single guide RNAs targeting genes whose inactivation enhanced accumulation of polymeric α1AT were enriched by iterative construction of CRISPR libraries based on genomic DNA from fixed cells selected for high polymer content by fluorescence-activated cell sorting. This approach bypassed the limitation to conventional enrichment schemes imposed by cell fixation. Results: Our screen identified 121 genes involved in polymer retention at false discovery rate < 0.1. From that set of genes, the pathway ‘cargo loading into COPII-coated vesicles’ was overrepresented with 16 significant genes, including two transmembrane cargo receptors, LMAN1 (ERGIG-53) and SURF4. LMAN1 and SURF4-disrupted cells displayed a secretion defect extended beyond α1AT monomers to polymers, whose low-level secretion was especially dependent on SURF4 and correlated with SURF4-α1AT-H334D physical interaction and with enhanced co-localisation of polymeric α1AT-H334D with the endoplasmic reticulum (ER). Conclusions: These findings suggest that ER cargo receptors co-ordinate intracellular progression of α1AT out of the ER and modulate the accumulation of polymeric α1AT not only by controlling the concentration of precursor monomers but also through a previously-unrecognised role in secretion of the polymers themselves.
2021-06-02 | GSE158574 | GEO
Project description:Individuals expressing alpha-1-antitrypsin mutant Z protein accumulate misfolded, mutant protein in the liver and are at risk for liver diseases including cirrhosis and hepatocellular carcinoma. Transgenic PiZ mice, a model for this liver disease, display similar pathologies to humans, including inflammation, increases in proliferation, autophagy and apoptosis, accumulation of globules and develop fibrosis and hepatocellular carcinoma with age. Microarrays were used to compare the gene expressions of PiZ mice to wild-type mice in order to identify the pathways that are altered in this disorder.
2012-11-08 | GSE36478 | GEO
Project description:Alpha-1 antitrypsin deficiency (AATD) is both a gain- and loss-of-function disease that impacts the liver and lung.1 Most severe cases result from a homozygous missense mutation in the SERPINA1 gene (Z mutation). While current therapies and those in development may ameliorate lung or liver disease, few are designed to address both.1 We have developed SERPINA1-994, a N-Acetylgalactosamine-conjugated chemically modified oligonucleotide that elicits adenine-to-inosine RNA editing using endogenous adenosine deaminases acting on RNA enzymes, to correct SERPINA1 Z transcripts. We show that SERPINA1-994 edits 50% of the Z transcript in hepatocytes of NSG-PiZ mice, which increases total serum AAT levels and induces the production of wild-type protein. SERPINA1-994 addresses loss of AAT function in lung by increasing the neutrophil elastase inhibition capacity of mouse serum and gain-of-function in liver by decreasing protein aggregation, decreasing inflammation and correcting gene expression patterns. SERPINA1-994 relies on a clinically proven delivery technology and directs highly specific RNA rather than DNA editing, so there is no risk for permanent off-target effects. Overall, these data suggest that SERPINA1-994 changes a ZZ homozygous state, which is associated with a high risk for AATD, to a low-risk MZ-like phenotype.
2026-01-12 | GSE267230 | GEO
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