{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:39:36Z","timestamp":1787503176398,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ISCIII -AESI","award":["PI20CIII\/00015"],"award-info":[{"award-number":["PI20CIII\/00015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The SERPINA1 gene encodes alpha1-antitrypsin (AAT), an acute phase glycoprotein and serine protease inhibitor that is mainly (80\u201390%) 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.<\/jats:p>","DOI":"10.3390\/ijms231810425","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T04:54:41Z","timestamp":1662699281000},"page":"10425","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Loss of Serpina1 in Mice Leads to Altered Gene Expression in Inflammatory and Metabolic Pathways"],"prefix":"10.3390","volume":"23","author":[{"given":"Sri Harsha","family":"Meghadri","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine, Platform Bioinformatics, Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6834-350X","authenticated-orcid":false,"given":"Beatriz","family":"Martinez-Delgado","sequence":"additional","affiliation":[{"name":"Functional Genomics Unit, Rare Diseases Research Institute, Carlos III Health Institute, 28220 Majadahonda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Ostermann","sequence":"additional","affiliation":[{"name":"Division of Experimental Pneumology, Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gema","family":"Gomez-Mariano","sequence":"additional","affiliation":[{"name":"Functional Genomics Unit, Rare Diseases Research Institute, Carlos III Health Institute, 28220 Majadahonda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Perez-Luz","sequence":"additional","affiliation":[{"name":"Functional Genomics Unit, Rare Diseases Research Institute, Carlos III Health Institute, 28220 Majadahonda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinu","family":"Tumpara","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Molecular Pneumology, Member of German Center for Lung Research (DZL), Biomedical Research School in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Wrenger","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Molecular Pneumology, Member of German Center for Lung Research (DZL), Biomedical Research School in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"DeLuca","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Platform Bioinformatics, Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich A.","family":"Maus","sequence":"additional","affiliation":[{"name":"Division of Experimental Pneumology, Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Welte","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Molecular Pneumology, Member of German Center for Lung Research (DZL), Biomedical Research School in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Janciauskiene","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Molecular Pneumology, Member of German Center for Lung Research (DZL), Biomedical Research School in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"881","DOI":"10.3324\/haematol.2008.004739","article-title":"Alpha1-antitrypsin Pittsburgh in a family with bleeding tendency","volume":"94","author":"Hua","year":"2009","journal-title":"Haematologica"},{"key":"ref_2","unstructured":"Sehgal, A., Bumcrot, D., and Bettencourt, B. (2012). Serpina1 Sirnas: Compositions of Matter and Methods of Treatment. (10935917B2), U.S. Patent."},{"key":"ref_3","first-page":"343","article-title":"Physical mapping of four serpin genes: Alpha 1-antitrypsin, alpha 1-antichymotrypsin, corticosteroid-binding globulin, and protein C inhibitor, within a 280-kb region on chromosome I4q32.1","volume":"52","author":"Billingsley","year":"1993","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2767","DOI":"10.1002\/j.1460-2075.1987.tb02571.x","article-title":"The human alpha 1-antitrypsin gene is transcribed from two different promoters in macrophages and hepatocytes","volume":"6","author":"Perlino","year":"1987","journal-title":"EMBO J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1042\/bst0300093","article-title":"Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin","volume":"30","author":"Kalsheker","year":"2002","journal-title":"Biochem. Soc. Trans."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Janciauskiene, S. (2013). Immunoregulatory Properties of Acute Phase Proteins\u2014Specific Focus on \u03b11-Antitrypsin. Acute Phase Proteins, Intechopen.","DOI":"10.5772\/56393"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s13148-021-01066-w","article-title":"Methylation of SERPINA1 gene promoter may predict chronic obstructive pulmonary disease in patients affected by acute coronary syndrome","volume":"13","author":"Rotondo","year":"2021","journal-title":"Clin. Epigenet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"550543","DOI":"10.3389\/fcell.2020.550543","article-title":"SERPINA1 Gene Promoter Is Differentially Methylated in Peripheral Blood Mononuclear Cells of Pregnant Women","volume":"8","author":"Rotondo","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1006\/geno.2002.6864","article-title":"The murine alpha(1)-proteinase inhibitor gene family: Polymorphism, chromosomal location, and structure","volume":"80","author":"Barbour","year":"2002","journal-title":"Genomics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e140816","DOI":"10.1172\/jci.insight.140816","article-title":"Alpha-1 antitrypsin deficiency impairs lung antibacterial immunity in mice","volume":"6","author":"Ostermann","year":"2021","journal-title":"JCI Insight"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.1073\/pnas.1713689115","article-title":"Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema","volume":"115","author":"Borel","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e12694","DOI":"10.1111\/acel.12694","article-title":"Anti-inflammaging effects of human alpha-1 antitrypsin","volume":"17","author":"Yuan","year":"2018","journal-title":"Aging Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cyto.2019.01.013","article-title":"The senescence-associated secretory phenotype and its regulation","volume":"117","author":"Rowell","year":"2019","journal-title":"Cytokine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1189\/jlb.0208145","article-title":"Alpha-1-antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood","volume":"85","author":"Pott","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E1418","DOI":"10.1210\/jc.2013-3864","article-title":"Alpha1-Antitrypsin therapy downregulates toll-like receptor-induced IL-1beta responses in monocytes and myeloid dendritic cells and may improve islet function in recently diagnosed patients with type 1 diabetes","volume":"99","author":"Gottlieb","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1096\/fj.00-0311com","article-title":"Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1","volume":"15","author":"Shapiro","year":"2001","journal-title":"FASEB J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R., and Ma\u2019ayan, A. (2013). Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-128"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: New perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41586-020-2496-1","article-title":"A single-cell transcriptomic atlas characterizes ageing tissues in the mouse","volume":"583","year":"2020","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1084\/jem.164.6.2006","article-title":"Amyloid A gene family expression in different mouse tissues","volume":"164","author":"Meek","year":"1986","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s10020-018-0047-0","article-title":"Serum amyloid A\u2014A review","volume":"24","author":"Sack","year":"2018","journal-title":"Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1194\/jlr.C061366","article-title":"SAA: A link between cholesterol efflux capacity and inflammation?","volume":"56","author":"Thomas","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.1074\/jbc.M411555200","article-title":"Serum amyloid A is a ligand for scavenger receptor class B type I and inhibits high density lipoprotein binding and selective lipid uptake","volume":"280","author":"Cai","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3690","DOI":"10.1210\/en.2013-1263","article-title":"The hepatic orosomucoid\/alpha1-acid glycoprotein gene cluster is regulated by the nuclear bile acid receptor FXR","volume":"154","author":"Porez","year":"2013","journal-title":"Endocrinology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6222","DOI":"10.1073\/pnas.0914904107","article-title":"Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates","volume":"107","author":"Cole","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.livres.2020.05.001","article-title":"Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis","volume":"4","author":"Chiang","year":"2020","journal-title":"Liver Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3608","DOI":"10.1038\/ncomms4608","article-title":"A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect","volume":"5","author":"Marcilla","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1194\/jlr.R037028","article-title":"Enzymology of retinoic acid biosynthesis and degradation","volume":"54","author":"Kedishvili","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1056\/NEJMoa2205416","article-title":"Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency","volume":"387","author":"Strnad","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1006\/bbrc.1996.0182","article-title":"The expression and characterization of five recombinant murine alpha 1-protease inhibitor proteins","volume":"219","author":"Paterson","year":"1996","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5354","DOI":"10.4049\/jimmunol.1400378","article-title":"Acute-phase protein alpha1-antitrypsin-a novel regulator of angiopoietin-like protein 4 transcription and secretion","volume":"192","author":"Frenzel","year":"2014","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1186\/s13059-019-1874-1","article-title":"Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression","volume":"20","author":"Hafemeister","year":"2019","journal-title":"Genome Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10425\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:28:02Z","timestamp":1760142482000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10425"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,9]]},"references-count":36,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231810425"],"URL":"https:\/\/doi.org\/10.3390\/ijms231810425","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,9]]}}}