ReviewVitamin B12 absorption: Mammalian physiology and acquired and inherited disorders
Highlights
► Dietary vitamin B12 absorption is a multistep process. ► Intestinal uptake of B12 requires Cubilin and Amnionless. ► B12 malabsorption results in a low vitamin status or a frank deficiency. ► A low vitamin B12 status increases the risk for deficiency. ► Frank B12 deficiency leads to hematological and neurological defects.
Introduction
The significance of vitamin B12 (cobalamin) adequate nutritional status throughout life span is established and the adverse effects of vitamin B12 deficiency in human health are currently recognized [1], [2], [3]. In addition to the well-described reversible hematological and often irreversible neurological changes of severe vitamin B12 deficiency, epidemiological studies revealed a more common condition, the low vitamin B12 status particularly in elder and pregnant women [4], [5], [6]. Because vitamin B12 is essential for DNA synthesis and cellular energy production, a low vitamin B12 status may be a risk factor for altered cellular metabolism and age-related diseases including cognitive decline and cardio-vascular disease [7]. The developing embryo may be particularly susceptible to vitamin B12 deficiency and a low maternal B12 status is believed to increase 2–4 fold the risk of neural tube closure defects [7], [8]. In this review we summarize current knowledge on the physiological and pathological aspects of vitamin B12 absorption in the ileum and its consequences on vitamin B12 status.
Section snippets
Vitamin B12
Vitamin B12 (a generic term for all cobalamins biologically active in man) is a water-soluble vitamin, with a molecular weight of 1355.4 Da [9]. It is made up by a central cobalt atom and a planar corrin ring (Fig. 1A). Cobalt is the functional part of vitamin B12. Diversity of the molecule that binds to the cobalt atom on the upper part of the corrin ring, including cyanide-, methyl- or deoxyadenosyl-groups gives rise to the various forms of vitamin B12 cyanocobalamin, methylcobalamin and
Vitamin B12 absorption
Mammals do not synthesize vitamin B12. Its presence in animal products is due to microbial synthesis and dietary intake of these products is the only natural source for man. The selective vitamin B12 absorption is a multistep process that involves the stomach, pancreas and small intestine (Fig. 1B). It is mediated by two carriers haptocorrin (HC) and intrinsic factor (IF), homologous proteins each carrying a single vitamin B12 molecule [16]. Malabsorption of vitamin B12 due to a dysfunction at
Causes of vitamin B12 deficiency
Assessing vitamin B12 status is challenging. The two biomarkers generally used are serum vitamin B12, which does not necessarily reflect tissue concentrations of the vitamin, and methylmalonic acid, a functional indicator of vitamin B12 status, which accumulates in the blood in the absence of adequate cobalamin levels. Despite its use to monitor vitamin B12 status, total serum homocystein levels are not in principle exclusively vitamin B12-dependent [46]. With the caveat that the levels of the
Conclusion
Biochemical and genetic approaches helped us to identify most of the gene products involved in the intestinal absorption of vitamin B12. Future research will show whether the same gene products, including the intestinal receptors of vitamin B12 CUBN and AMN and/or LRP2 are also involved in vitamin B12 transport in the central nervous system and/or the placenta. However, because ∼20% of the currently known cases with inherited intestinal vitamin B12 malabsorption remain unexplained additional
References (62)
How common is vitamin B-12 deficiency?
Am. J. Clin. Nutr.
(2009)- et al.
B vitamin status, dietary intake and length of stay in a sample of elderly rehabilitation patients
J. Nutr. Health Aging
(2011) - et al.
Vitamin B(12) and birth defects
Mol. Genet. Metab.
(2009) - et al.
The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin
Blood
(2009) - et al.
The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region
Blood
(1998) - et al.
The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins
J. Biol. Chem.
(1998) - et al.
Molecular dissection of the intrinsic factor-vitamin B12 receptor, cubilin, discloses regions important for membrane association and ligand binding
J. Biol. Chem.
(1999) - et al.
Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo
Blood
(2005) - et al.
Vitamin B12 deficiency with normal Schilling test or non-dissociation of vitamin B12 and its carrier proteins in elderly patients. A study of 60 patients
Rev. Med. Interne
(2003) - et al.
Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin
Blood
(2010)
Biomarkers of vitamin B-12 status in NHANES: a roundtable summary
Am. J. Clin. Nutr.
Monitoring of vitamin B-12 nutritional status in the United States by using plasma methylmalonic acid and serum vitamin B-12
Am. J. Clin. Nutr.
B12 in fetal development
Semin. Cell. Dev. Biol.
Malabsorption of food cobalamin
Baillieres Clin. Haematol.
The disappearance of cobalamin absorption testing: a critical diagnostic loss
J. Nutr.
In vitro and in vivo evidences that the malabsorption of cobalamin is related to its binding on haptocorrin (R binder) in chronic pancreatitis
Am. J. Clin. Nutr.
Metformin and digestive disorders
Diabetes Metab.
Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin
Blood
Indicators for assessing folate and vitamin B12 status and for monitoring the efficacy of intervention strategies
Food Nutr. Bull.
Subclinical cobalamin deficiency
Curr. Opin. Gastroenterol.
Vitamin B12 transport from food to the body's cells–a sophisticated, multistep pathway
Nat. Rev. Gastroenterol. Hepatol.
Vitamin B12 metabolism and status during pregnancy, lactation and infancy
Adv. Exp. Med. Biol.
Vitamin B12 in health and disease
Nutrients
Vitamin B12 sources and bioavailability
Exp. Biol. Med. (Maywood)
Vitamin B12-derivatives-enzyme cofactors and ligands of proteins and nucleic acids
Chem. Soc. Rev.
Assessment of vitamin B(12) absorption based on the accumulation of orally administered cyanocobalamin on transcobalamin
Clin. Chem.
Biochemistry of B12-cofactors in human metabolism
Subcell. Biochem.
Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases
J. Physiol. Pharmacol.
Homocysteine, S-adenosylmethionine and S-adenosylhomocysteine are associated with retinal microvascular abnormalities: the Hoorn Study
Clin. Sci. (Lond)
Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB)
Pediatr. Res.
A single rainbow trout cobalamin-binding protein stands in for three human binders
J. Biol. Chem.
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2024, International Journal of Biological MacromoleculesCD320 expression and apical membrane targeting in renal and intestinal epithelial cells
2022, International Journal of Biological MacromoleculesCitation Excerpt :Inadequate dietary intake and poor absorption are common causes of vitamin B12 deficiency, which can lead to hematological and neurological disorders such as megaloblastic anemia, paresthesia, ataxia, and cognitive dysfunction [1–5]. CD320, also known as transcobalamin receptor, is the receptor responsible for cellular uptake of vitamin B12 in tissues [1,2,6–8]. Following the absorption in the intestine, vitamin B12 enters intercellular fluid and the circulation, where it forms a complex with its carrier protein, transcobalamin 2 (TCN2).