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Transcriptomic analyses of the effects of hepatic insulin signaling on hepatic gene expression in the PiZ mouse model of alpha-1-antitrypsin deficiency liver disease

ABSTRACT: Transcriptomic analyses of the effects of hepatic insulin signaling on hepatic gene expression in the PiZ mouse model of alpha-1-antitrypsin deficiency liver disease

PROVIDER: PRJNA743657 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15037800.fastq.gz	Fastqsanger.gz
	SRR15037900_1.fastq.gz	Fastqsanger.gz
	SRR15037900_2.fastq.gz	Fastqsanger.gz
	SRR15037801.fastq.gz	Fastqsanger.gz
	SRR15037901_1.fastq.gz	Fastqsanger.gz

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Transcriptomic analyses of the effects of hepatic insulin signaling on hepatic gene expression in the PiZ mouse model of alpha-1-antitrypsin deficiency liver disease

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Project description:In this study, we sought to thoroughly characterize the liver pathophysiology of a human transgenic mouse model for alpha-1 antitrypsin deficiency (AATD) with a strong manifestation of AATD-mediated liver disease. Male and female transgenic mice for normal variant human alpha-1 antitrypsin (Pi*M) and mutant human alpha-1 antitrypsin (Pi*Z) at 3 and 6 months of age with a C57BL/6J background were subjected to study. The progression of hepatic accumulation of mutant alpha-1 antitrypsin (ZAAT), hepatocyte injury, steatosis, liver inflammation and fibrotic features of this mouse model were monitored by performing an in vivo study.

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Gene expression profile of wild type, PiZ and PiZ/Chop-/- mouse livers at two different ages

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

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Gene Expression Levels in PiZ mice Compared to Wild-type (Wt)C57Bl/6

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

Gene Expression Levels in PiZ mice Compared to Wild-type (Wt)C57Bl/6

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The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study (GRADS) Alpha-1 study [A1AT]

Project description:Whole genome mRNA and microRNA profiling of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cell (PBMC) in Alpha-1 Antitrypsin Deficiency patients with PiZZ or PiMZ alpha-1 antitrypsin genotypes

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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.

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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.

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