title: Hepatic adaptation compensates inactivation of intestinal arginine biosynthesis in suckling mice.
abstract: Suckling mammals, including mice, differ from adults in the abundant expression of enzymes that synthesize arginine from citrulline in their enterocytes. To investigate the importance of the small-intestinal arginine synthesis for whole-body arginine production in suckling mice, we floxed exon 13 of the argininosuccinate synthetase (Ass) gene, which codes for a key enzyme in arginine biosynthesis, and specifically and completely ablated Ass in enterocytes by crossing Ass (fl) and Villin-Cre mice. Unexpectedly, Ass (fl/fl) /VilCre (tg/-) mice showed no developmental impairments. Amino-acid fluxes across the intestine, liver, and kidneys were calculated after determining the blood flow in the portal vein, and hepatic and renal arteries (86%, 14%, and 33%, respectively, of the transhepatic blood flow in 14-day-old mice). Relative to control mice, citrulline production in the splanchnic region of Ass (fl/fl) /VilCre (tg/-) mice doubled, while arginine production was abolished. Furthermore, the net production of arginine and most other amino acids in the liver of suckling control mice declined to naught or even changed to consumption in Ass (fl/fl) /VilCre (tg/-) mice, and had, thus, become remarkably similar to that of post-weaning wild-type mice, which no longer express arginine-biosynthesizing enzymes in their small intestine. The adaptive changes in liver function were accompanied by an increased expression of genes involved in arginine metabolism (Asl, Got1, Gpt2, Glud1, Arg1, and Arg2) and transport (Slc25a13, Slc25a15, and Slc3a2), whereas no such changes were found in the intestine. Our findings suggest that the genetic premature deletion of arginine synthesis in enterocytes causes a premature induction of the post-weaning pattern of amino-acid metabolism in the liver.
authors.affiliation: Department of Anatomy & Embryology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Vincent
authors.initials: V
authors.lastname: Marion
authors.forename: Selvakumari
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Chiel
authors.initials: C
authors.lastname: de Theije
authors.forename: Paul
authors.initials: P
authors.lastname: van Dijk
authors.forename: Theo B M
authors.initials: TB
authors.lastname: Hakvoort
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
authors.forename: Eleonore S
authors.initials: ES
authors.lastname: Köhler
mesh_terms: D000220:Adaptation, Biological; D000596:Amino Acids / Q000097:blood / Q000378:metabolism; D000818:Animals; D000833:Animals, Suckling / Q000502:physiology*; D001120:Arginine / Q000096:biosynthesis*; D001124:Argininosuccinate Synthase / Q000235:genetics; D001692:Biological Transport; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D000596:Amino Acids; D001120:Arginine; D001124:Argininosuccinate Synthase