L-Arginine Availability and Metabolism Is Altered in Ulcerative Colitis.
L-arginine (L-Arg) is the substrate for both inducible nitric oxide (NO) synthase (NOS2) and arginase (ARG) enzymes. L-Arg is actively transported into cells by means of cationic amino acid transporter (SLC7) proteins. We have linked L-Arg and arginase 1 activity to epithelial restitution. Our aim was to determine if L-Arg, related amino acids, and metabolic enzymes are altered in ulcerative colitis (UC).



Serum and colonic tissues were prospectively collected from 38 control subjects and 137 UC patients. Dietary intake, histologic injury, and clinical disease activity were assessed. Amino acid levels were measured by high-performance liquid chromatography. Messenger RNA (mRNA) levels were measured by real-time PCR. Colon tissue samples from 12 Crohn's disease patients were obtained for comparison.



Dietary intake of arginine and serum L-Arg levels were not different in UC patients versus control subjects. In active UC, tissue L-Arg was decreased, whereas L-citrulline (L-Cit) and the L-Cit/L-Arg ratio were increased. This pattern was also seen when paired involved (left) versus uninvolved (right) colon tissues in UC were assessed. In active UC, SLC7A2 and ARG1 mRNA levels were decreased, whereas ARG2 and NOS2 were increased. Similar alterations in mRNA expression occurred in tissues from Crohn's disease patients. In involved UC, SLC7A2 and ARG1 mRNA levels were decreased, and NOS2 and ARG2 increased, when compared with uninvolved tissues.



Patients with UC exhibit diminished tissue L-Arg, likely attributable to decreased cellular uptake and increased consumption by NOS2. These findings combined with decreased ARG1 expression indicate a pattern of dysregulated L-Arg availability and metabolism in UC.
*Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee;†Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;‡Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee;§University of Central Florida, College of Medicine, Orlando, Florida;‖Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; and¶Vanderbilt Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee.
Lori A
LA
Coburn
Sara N
SN
Horst
Margaret M
MM
Allaman
Caroline T
CT
Brown
Christopher S
CS
Williams
Mallary E
ME
Hodges
Jennifer P
JP
Druce
Dawn B
DB
Beaulieu
David A
DA
Schwartz
Keith T
KT
Wilson
D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D000596:Amino Acids / Q000378:metabolism*; D001119:Arginase / Q000235:genetics; D001120:Arginine / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D001682:Biological Availability; D016022:Case-Control Studies; D002956:Citrulline / Q000378:metabolism; D002986:Clinical Trials as Topic; D003093:Colitis, Ulcerative / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism*; D003424:Crohn Disease / Q000378:metabolism; D015930:Diet Records; D006801:Humans; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism*; D012720:Severity of Illness Index
D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D012333:RNA, Messenger; C414177:SLC7A2 protein, human; D002956:Citrulline; D001120:Arginine; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D001119:Arginase