title: Argininosuccinate lyase in enterocytes protects from development of necrotizing enterocolitis.
abstract: Necrotizing enterocolitis (NEC), the most common neonatal gastrointestinal emergency, results in significant mortality and morbidity, yet its pathogenesis remains unclear. Argininosuccinate lyase (ASL) is the only enzyme in mammals that is capable of synthesizing arginine. Arginine has several homeostatic roles in the gut and its deficiency has been associated with NEC. Because enterocytes are the primary sites of arginine synthesis in neonatal mammals, we evaluated the consequences of disruption of arginine synthesis in the enterocytes on the pathogenesis of NEC. We devised a novel approach to study the role of enterocyte-derived ASL in NEC by generating and characterizing a mouse model with enterocyte-specific deletion of Asl (Asl(flox/flox); VillinCre(tg/+), or CKO). We hypothesized that the presence of ASL in a cell-specific manner in the enterocytes is protective in the pathogenesis of NEC. Loss of ASL in enterocytes resulted in an increased incidence of NEC that was associated with a proinflammatory state and increased enterocyte apoptosis. Knockdown of ASL in intestinal epithelial cell lines resulted in decreased migration in response to lipopolysaccharide. Our results show that enterocyte-derived ASL has a protective role in NEC.
authors.affiliation: Division of Neonatology, Texas Children's Hospital, Baylor College of Medicine;
authors.forename: M H
authors.initials: MH
authors.lastname: Premkumar
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: G
authors.initials: G
authors.lastname: Sule
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: S C
authors.initials: SC
authors.lastname: Nagamani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: S
authors.initials: S
authors.lastname: Chakkalakal
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: A
authors.initials: A
authors.lastname: Nordin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: M
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: M Z
authors.initials: MZ
authors.lastname: Ruan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: T
authors.initials: T
authors.lastname: Bertin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: B
authors.initials: B
authors.lastname: Dawson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston;
authors.forename: D
authors.initials: D
authors.lastname: Schady
authors.affiliation: University of Texas Health Science Center at Houston, Texas;
authors.forename: N S
authors.initials: NS
authors.lastname: Bryan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine;
authors.forename: P M
authors.initials: PM
authors.lastname: Campeau
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel; and.
authors.forename: A
authors.initials: A
authors.lastname: Erez
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine; Howard Hughes Medical Institute, Houston, Texas blee@bcm.edu.
authors.forename: B
authors.initials: B
authors.lastname: Lee
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001123:Argininosuccinate Lyase / Q000235:genetics / Q000378:metabolism*; D056807:Argininosuccinic Aciduria / Q000201:enzymology / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D020895:Enterocytes / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D041943:Infant Formula; D007231:Infant, Newborn; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D034622:RNA Interference; D051381:Rats; D013997:Time Factors; D014162:Transfection
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; C577686:interleukin-6, mouse; D001123:Argininosuccinate Lyase
keywords: ASL; NEC; arginine