Loss of Serpina1 in Mice Leads to Altered Gene Expression in Inflammatory and Metabolic Pathways
| Autor: | Sri Harsha Meghadri, Beatriz Martinez-Delgado, Lena Ostermann, Gema Gomez-Mariano, Sara Perez-Luz, Srinu Tumpara, Sabine Wrenger, David S. DeLuca, Ulrich A. Maus, Tobias Welte, Sabina Janciauskiene |
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| Přispěvatelé: | Instituto de Salud Carlos III |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Serine Proteinase Inhibitors
Data analysis Gene Expression liver SERPINA mice gene knockout RNA sequencing transcriptomics metabolism single-cell alpha1-antitrypsin protein misfolding data analysis Gene knockout Catalysis Inorganic Chemistry Mice alpha 1-Antitrypsin Deficiency Animals Humans RNA Small Interfering Physical and Theoretical Chemistry Transcriptomics Molecular Biology Spectroscopy Single-cell Organic Chemistry General Medicine Computer Science Applications Mice Inbred C57BL Metabolism Cholesterol Liver alpha 1-Antitrypsin Alpha1-antitrypsin Metabolic Networks and Pathways Protein misfolding |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 18; Pages: 10425 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms231810425 |
| Popis: | The SERPINA1 gene encodes alpha1-antitrypsin (AAT), an acute phase glycoprotein and serine protease inhibitor that is mainly (80-90%) produced in the liver. Point mutations in the SERPINA1 gene can lead to the misfolding, intracellular accumulation, and deficiency of circulating AAT protein, increasing the risk of developing chronic liver diseases or chronic obstructive pulmonary disease. Currently, siRNA technology can knock down the SERPINA1 gene and limit defective AAT production. How this latter affects other liver genes is unknown. Livers were taken from age- and sex-matched C57BL/6 wild-type (WT) and Serpina1 knockout mice (KO) aged from 8 to 14 weeks, all lacking the five serpin A1a-e paralogues. Total RNA was isolated and RNA sequencing, and transcriptome analysis was performed. The knockout of the Serpina1 gene in mice changed inflammatory, lipid metabolism, and cholesterol metabolism-related gene expression in the liver. Independent single-cell sequencing data of WT mice verified the involvement of Serpina1 in cholesterol metabolism. Our results from mice livers suggested that designing therapeutic strategies for the knockout of the SERPINA1 gene in humans must account for potential perturbations of key metabolic pathways and consequent mitigation of side effects. RNA sequencing was supported by the grant ISCIII-AESI PI20CIII/00015. Sí |
| Databáze: | OpenAIRE |
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