Vitamin C transporter Slc23a1 links renal   reabsorption, vitamin C tissue accumulation,   and perinatal survival in mice.
Levels of the necessary nutrient vitamin C (ascorbate) are tightly regulated by intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Ascorbate levels are controlled in part by regulation of transport through at least 2 sodium-dependent transporters: Slc23a1 and Slc23a2 (also known as Svct1 and Svct2, respectively). Previous work indicates that Slc23a2 is essential for viability in mice, but the roles of Slc23a1 for viability and in adult physiology have not been determined. To investigate the contributions of Slc23a1 to plasma and tissue ascorbate concentrations in vivo, we generated Slc23a1-/- mice. Compared with wild-type mice, Slc23a1-/- mice increased ascorbate fractional excretion up to 18-fold. Hepatic portal ascorbate accumulation was nearly abolished, whereas intestinal absorption was marginally affected. Both heterozygous and knockout pups born to Slc23a1-/- dams exhibited approximately 45% perinatal mortality, and this was associated with lower plasma ascorbate concentrations in dams and pups. Perinatal mortality of Slc23a1-/- pups born to Slc23a1-/- dams was prevented by ascorbate supplementation during pregnancy. Taken together, these data indicate that ascorbate provided by the dam influenced perinatal survival. Although Slc23a1-/- mice lost as much as 70% of their ascorbate body stores in urine daily, we observed an unanticipated compensatory increase in ascorbate synthesis. These findings indicate a key role for Slc23a1 in renal ascorbate absorption and perinatal survival and reveal regulation of vitamin C biosynthesis in mice.
Corpe
Christopher P
CP
Molecular and Clinical Nutrition Section, Digestive Diseases Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA.
Tu
Hongbin
H
Eck
Peter
P
Wang
Jin
J
Faulhaber-Walter
Robert
R
Schnermann
Jurgen
J
Margolis
Sam
S
Padayatty
Sebastian
S
Sun
He
H
Wang
Yaohui
Y
Nussbaum
Robert L
RL
Espey
Michael Graham
MG
Levine
Mark
M
D000042:Absorption; D000818:Animals; D000831:Animals, Newborn; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000502:physiology*; D054238:Perinatal Mortality; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters / Q000235:genetics / Q000502:physiology*
D029363:Organic Anion Transporters, Sodium-Dependent; C555164:Slc23a1 protein, mouse; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters; D001205:Ascorbic Acid