Transcobalamin II synthesized in the intestinal villi facilitates transfer of cobalamin to the portal blood

Abstract

This study was designed to identify the cellular component of the intestinal villus where transcobalamin II (TCII) is synthesized, because this protein provides an essential function in the intestinal absorption of vitamin B12 (cobalamin, Cbl). When a segment of proximal or distal small intestine of the guinea pig is cultured in medium containing [57Co]Cbl, TCII-[57Co]Cbl appears within 15 min. Northern blot analysis of RNA from both proximal and distal small intestine identified the TCII transcript. In situ hybridization of the distal ileum with35S-labeled TCII antisense transcript localized grains predominantly in crypts and in the lower third and central core of the villi. Grains were also evident at the base of the enterocytes in close apposition with the vascular network, whereas few grains appeared in the apical region of the columnar cells. This study provides evidence that TCII is constitutively expressed in the intestinal villi where vascular endothelium is abundant. In the distal ileum, where the intrinsic factor (IF) receptor is expressed, after uptake of IF-Cbl and the subsequent binding of free Cbl to TCII synthesized in the villi, the TCII-Cbl complex enters the microcirculation and passes into the portal blood.

Vitamin B-12 and Perinatal Health

“…Vitamin B-12 dissociates from IF in endothelial cells and enters portal circulation bound to transcobalamin (TC). Although most vitamin B-12 is bound to haptocorrin, TCbound vitamin B-12 is delivered to the liver and other tissues where it is taken up by a TC receptor protein (23)(24)(25). The physiologic role of haptocorrin in circulation remains unclear, although haptocorrin may act as a scavenger protein to remove inactive vitamin B-12 analogs from circulation (26,27).…”

Structural basis for mammalian vitamin B 12 transport by transcobalamin

“…After proteolysis of HC-Cbl and other protein complexes of dietary Cbl in the duodenum, Cbl binds to intrinsic factor (IF) in the proximal ileum. The IF-Cbl complex enters mucosal cells in the distal ileum by receptor-mediated endocytosis, and Cbl is transferred to transcobalamin II (TC) (5), whose suggested source is the vascular endothelium (5), and which is the only nonglycosylated protein among the transporters. TCCbl is released to the plasma and enters cells by endocytosis via a receptor of as-yet-controversial identity (4).…”

Crystal structure of human intrinsic factor: Cobalamin complex at 2.6-Å resolution

“…Human IF contains 399-aa residues plus Ϸ15% carbohydrate, giving it a molecular mass of Ϸ60 kDa, as observed by gel filtration (10-13). All three proteins promote Cbl entry through endocytosis involving distinct cell surface receptors (5,(14)(15)(16)(17)(18)(19)(20).Dietary Cbl is bound first to HC in the gastric lumen but is transferred to IF in the duodenum after degradation of HC by pancreatic proteases. IF is responsible for transit of Cbl through the small intestine and delivery of it to the endothelial cells that line the ileum.…”

“…Human IF contains 399-aa residues plus Ϸ15% carbohydrate, giving it a molecular mass of Ϸ60 kDa, as observed by gel filtration (10-13). All three proteins promote Cbl entry through endocytosis involving distinct cell surface receptors (5,(14)(15)(16)(17)(18)(19)(20).…”