Accumulation of mutant Z α1-Antitrypsin impairs intestinal function in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE291017 | GEO | 2026/06/29
REPOSITORIES: GEO
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Project description:Accumulation of mutant Z α1-Antitrypsin impairs intestinal function in mice
| PRJNA1231408 | ENA
Project description:Cargo receptor-assisted endoplasmic reticulum export of pathogenic α1-antitrypsin polymers
| PRJNA665693 | ENA
Project description:Alpha1-antitrypsin (AAT) mutations cause retention of the otherwise secreted protein and lead to the proteotoxic AAT deficiency (AATD)-related liver disease (AATD-LD). As mechanistic target of rapamycin (mTOR) is a key coordinator of proteostasis, we studied its role in AATD-LD. PiZ mice overexpressing the characteristic AAT mutation were mated with rodents harboring a hepatocyte specific-ablation of the interaction partners regulatory-associated protein of mTOR (RAPTOR) or rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) corresponding to mTOR complexes 1 or 2 (mTORC1/2) or with mice lacking mTOR. At two month of age, PiZ-mTORΔhep and PiZ-RaptorΔhep but not PiZ-RictorΔhep mice showed signs of increased liver injury and increased mortality despite diminished AAT accumulation. PiZ-RaptorΔhep animals displayed increased levels of the pro-apoptotic protein C/EBP homologous protein (CHOP), but CHOP ablation did not rescue the phenotype. Serum proteomics revealed no signs of an advanced synthetic liver failure but immature hepatocellular products. Liver bulk proteomics and liver small metabolite measurement demonstrated a metabolic reprogramming of PiZ-RaptorΔhep mice. Spatial proteomics revealed alterations in liver zonation with increased ammonia levels as the likely cause of death in PiZ-RaptorΔhep animals. In conclusion, in AATD-related proteotoxic liver injury, Raptor preserves a liver zonation thereby protecting from lethal metabolic dysregulation.
2026-09-14 | PXD061881 | Pride
Project description:Liver disease in Alpha-1 antitrypsin deficiency (AATD) is caused by the toxic accumulation of mutant Z alpha-1 antitrypsin (Z-AAT) within the endoplasmic reticulum (ER) of hepatocytes. Both liver tissues from AATD patients and livers from PiZ transgenic mice expressing the human Z-AAT exhibit increased levels of p62/SQSTM1, a multifunctional protein involved in protein homeostasis and tumorigenesis. In PiZ mouse livers, p62/SQSTM1 decorates ubiquitin-positive, Periodic-Acid Shiff-diastase- resistant Z-AAT globules and physically interacts with Z-AAT. Genetic ablation of p62/SQSTM1 in PiZ mice (PiZ/p62-/-) led to a marked reduction in hepatic Z-AAT globules and polymers, as well as decreased serum Z-AAT levels, highlighting a central role for p62/SQSTM1 in disease pathogenesis. In conclusion, our study identifies p62/SQSTM1 as a critical mediator of Z-AAT-induced liver injury and reveals new potential therapeutic targets for the treatment of AATD-related liver disease.
2026-09-21 | PXD066413 | Pride
Project description:Alpha1-antitrypsin (AAT) mutations lead to the retention of the otherwise secreted protein thereby giving rise to AAT deficiency (AATD). AATD-related liver disease (AATD-LD) arises due to the proteotoxic stress and is the second leading cause of mortality in AATD with no approved pharmacologic treatment options. Since mechanistic target of rapamycin (mTOR) signalling constitutes a key coordinator of proteostasis, we studied its role in the development of AATD-LD. PiZ mice overexpressing the clinically most relevant AAT mutation were mated with rodents harbouring a hepatocyte specific-ablation of the interaction partners regulatory-associated protein of mTOR (RAPTOR) or rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) corresponding to mTOR complexes 1 or 2 (mTORC1/2) or with mice lacking mTOR. At two month of age, PiZ-mTORΔhep and PiZ-RaptorΔhep but not PiZ-RictorΔhep mice showed signs of liver injury and increased mortality. While PiZ-RaptorΔhep animals displayed elevated levels of the pro-apoptotic protein C/EBP homologous protein (CHOP), CHOP ablation did not rescue the phenotype. Although bulk liver proteomics displayed a decrease in key regenerative pathways, serum proteomics revealed no signs of markedly impaired liver function. Since bulk proteomics and assessment of hepatic metabolites pointed towards metabolic reprogramming of PiZ-RaptorΔhep mice, a spatial liver proteomics was carried out. The latter revealed alterations in liver zonation that was particularly prominent in the pericentral zone. Immunostaining confirmed a distinct loss of pericentral cells and further studies revealed hyperammonemia as the likely cause of death.
2026-09-14 | PXD053427 | Pride
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 p62 in the pathogenesis of liver disease due to Z alpha-1 antitrypsin in juvenile and older mice, we performed Quant-seq experiments at 36 weeks of age in wild type, PiZ and PiZ/p62-/- mouse livers
2026-09-23 | GSE182961 | GEO
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