RT Journal Article
T1 Loss of Serpina1 in Mice Leads to Altered Gene Expression in Inflammatory and Metabolic Pathways
A1 Pérez Luz, Sara
A1 Meghadri, Sri Harsha
A1 Martinez-Delgado, Beatriz
A1 Ostermann, Lena
A1 Gomez-Mariano, Gema
A1 Tumpara, Srinu
A1 Wrenger, Sabine
A1 DeLuca, David
A1 Maus, Ulrich A.
A1 Welte, Tobias
A1 Janciauskiene, Sabina
AB 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.
PB MDPI
YR 2022
FD 2022-09-09
LK https://hdl.handle.net/20.500.14352/102051
UL https://hdl.handle.net/20.500.14352/102051
LA eng
NO Meghadri, S.H.; Martinez-Delgado, B.; Ostermann, L.; Gomez-Mariano, G.; Perez-Luz, S.; Tumpara, S.; Wrenger, S.; DeLuca, D.S.; Maus, U.A.; Welte, T.; et al. Loss of Serpina1 in Mice Leads to Altered Gene Expression in Inflammatory and Metabolic Pathways. Int. J. Mol. Sci. 2022, 23, 10425. https:// doi.org/10.3390/ijms231810425
NO Author Contributions: S.J., D.S.D. and S.H.M. conceptualized this project; B.M.-D., U.A.M., L.O., G.G.- M. and S.P.-L. contributed to the methodology; D.S.D. and S.H.M. performed the computational analysis; S.T. and S.W. contributed to the formal analysis and investigation. Resources were provided by S.J., B.M.-D., U.A.M. and T.W. The original draft was prepared by D.S.D., S.H.M. and S.J., D.S.D., S.H.M., S.W., S.J., T.W. and U.A.M. reviewed the manuscript. The project was supervised by D.S.D. and S.J. All authors have read and agreed to the published version of the manuscript.
DS Docta Complutense
RD 12 abr 2025