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Liver organoids generated from individuals carrying PiZZ variant of alpha-1-antitrypsin contain high lipid content

ABSTRACT: We generated hepatic organoids from MZ and ZZ patients with the aim to investigate their lipid status To discover genes related to lipid metabolism likely involved in lipid deposits.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220537 | GEO | 2023/12/31

REPOSITORIES: GEO

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Liver organoids generated from individuals carrying PiZZ variant of alpha-1-antitrypsin contain high lipid content

Project description:Liver organoids generated from individuals carrying PiZZ variant of alpha-1-antitrypsin contain high lipid content

| PRJNA910152 | ENA

Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysfunction and Cellular Heterogeneity in PiMZ and PiZZ Hepatic Cells (bulk RNA-Seq)

Project description:We profiled the global transcriptomes of PiZZ6 syngenenic ZZ, MZ, and MM iPSCs that underwent directed differentiation to the hepatic lineage using RNA sequencing.

2022-12-06 | GSE198233 | GEO

Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysfunction and Cellular Heterogeneity in PiMZ and PiZZ Hepatic Cells (scRNA-Seq)

Project description:Individuals homozygous for the "Z" mutation in alpha-1 antitrypsin deficiency are known to be at increased risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the heterozygous state. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. Here, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps). We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell subpopulations. Our model of MZ heterozygosity thus provides evidence that a single Z allele is sufficient to disrupt hepatocyte homeostatic function.

2022-12-06 | GSE198234 | GEO

DNA methylome profiling of blood to identify individuals in a pair of monozygotic twins

Project description:Short tandem repeat (STR) markers cannot be used to distinguish between genetically identical monozygotic (MZ) twins, causing problems in a case with an MZ twin as a suspect. Many studies have shown that in older MZ twins, there are significant differences in overall content and genomic distribution of methylation

2023-09-27 | GSE225544 | GEO

Alterations in lysosomal gene expression and lipid homeostasis in patient-derived liver organoids with acid sphingomyelinase deficiency

Project description:We generated hepatic organoids from Nieman Pick Type B patients with the aim to investigate their lipid status. To discover genes related to lipid metabolism likely involved in lipid deposits.

2023-07-04 | GSE236213 | GEO

Cell Autonomous Lipid Handling Defects in Stargardt iPS Cell-Derived Retinal Pigment Epithelium Cells

Project description:Stargardt retinopathy is an inherited form of macular degeneration caused by mutations in gene ABCA4 and characterized by the accumulation of lipid-rich deposits in the retinal pigment epithelium (RPE), RPE atrophy, and photoreceptor cell death. Inadequate mechanistic insights into pathophysiological changes occurring in Stargardt RPE have contributed to its lacking treatments. Here we show that ABCA4 knockout or Stargardt patient’s induced pluripotent stem cells-derived RPE (STGD1-iRPE) differentiate normally but display intracellular lipid and ceramide deposits reminiscent of the disease phenotype. STGD1-iRPE also shows defective photoreceptor outer segment (POS) processing and reduced cathepsin B activity, indicating higher lysosomal pH. Lipid deposits in STGD1-iRPE are reduced by increasing the activity of ABCA1, a lipid transporter, and ABCA4 ortholog. Overall, our work suggests that ABCA4 is involved in POS and lipid handling in RPE cells and provides guidance for ongoing gene therapy approaches to target both RPE and photoreceptor cells for an effective treatment.

2022-11-16 | GSE198362 | GEO

Low Gluten Beers Contain Variable Gluten and Immunogenic Epitope Content.

Project description:Gluten content labels inform food choice and people practicing a gluten-free diet rely upon them to avoid illness. The regulations differ between jurisdictions, especially concerning fermented foodstuffs such as beer. Gluten abundance is typically measured using ELISAs, which have come into question when testing fermented or hydrolysed foodstuffs such as beer. Mass spectrometry can be used to directly identify gluten peptides and reveal false negatives recorded by ELISA. In this survey of gluten in control and gluten-free beers, gluten protein fragments that contain known immunogenic epitopes were detected using liquid chromatography-mass spectrometry in multiple beers that claim to be gluten-free and have sufficiently low gluten content, as measured by ELISA, to qualify as being gluten-free in some jurisdictions. In fact, several purportedly gluten-free beers showed equivalent or higher hordein content than some of the untreated, control beers. The shortcomings of ELISAs for beer gluten testing are summarised, the mismatch between ELISA and mass spectrometry results are explored, and the suitability of existing regulations as they pertain to the gluten content in fermented foods in different jurisdictions are discussed.

| S-EPMC10486350 | biostudies-literature

Clinical considerations in individuals with ?1-antitrypsin PI*SZ genotype.

Project description:?1-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of ?1-antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. In addition, the relevance of the putative 11?µM "protective threshold" for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals.

| S-EPMC7301289 | biostudies-literature

Proteomic analysis of in situ formalin-fixed paraffin-embedded (FFPE) human liver tissues

Project description:in situ proteomic analysis (combining laser microdissection of hepatocytes and mass spectrometry analysis) on formalin-fixed paraffin-embedded (FFPE) human liver tissues of 4 ZZ-Alpha 1-Antitrypsin Deficiency (AATD) pediatric patients and 4 ZZ-AATD adult patients that underwent liver transplantation versus 3 WT individuals infants and 4 adults, and compared proteins differentially expressed in ZZ pediatric and in ZZ adult AATD patients.

2021-09-09 | PXD022994 | Pride

The ZZ-type zinc finger of ZZZ3 modulates the ATAC complex-mediated histone acetylation and gene activation

Project description:Recognition of post-translational modifications on histones by epigenetic readers is a fundamental mechanism for the regulation of chromatin and transcription. Compared to the large number of readers that recognize histone methylation, only a few acetyllysine readers have been identified, including bromodomain, YEATS, and double plant homeodomain zinc finger (DPF). Here, we report the identification of a novel reader of histone H3, the ZZ-type zinc finger (ZZ) domain of ZZZ3, a subunit of the Ada-Two-A Containing (ATAC) histone acetyltransferase complex. The solution NMR structure of the ZZ in complex with the H3 peptide reveals a unique histone-binding mechanism involving caging of the N-terminal Alanine 1 of histone H3 in an acidic cavity of the ZZ domain. Importantly, acetylation on Lysine 4 of H3 (H3K4ac) enhances the binding, and in cells, ZZZ3 colocalizes with H3K4ac across the genome. The recognition of histone acetylation by ZZ is essential for chromatin occupancy of ZZZ3 and functions of the ATAC complex. Depletion of ZZZ3 or disruption of the ZZ-H3 interaction dampens ATAC dependent promoter histone H3K9 acetylation and the expression of ribosomal protein encoding genes. Overall, our study identifies the ZZ domain of ZZZ3 as a novel epigenetic reader that links the GCN5/ATAC complex to histone acetylation.

2018-09-14 | GSE100009 | GEO

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