Gastric intrinsic factor: The gastric and small intestinal stages of cobalamin absorption. A personal journey

Biochimie ◽  
2013 ◽  
Vol 95 (5) ◽  
pp. 989-994 ◽  
Author(s):  
David H. Alpers ◽  
Greg Russell-Jones
Keyword(s):  
Intrinsic Factor ◽  
Personal Journey ◽  
Small Intestinal ◽  
Cobalamin Absorption

Intrinsic factor-mediated intestinal absorption of cobalamin in the dog

1981 ◽  
Vol 241 (4) ◽  
pp. G294-G299 ◽  
Author(s):  
G. Marcoullis ◽  
S. P. Rothenberg
Keyword(s):  
Intestinal Absorption ◽  
Intrinsic Factor ◽  
Physicochemical Analysis ◽  
Significant Fraction ◽  
Receptor Protein ◽  
Ileal Mucosa ◽  
Membrane Bound ◽  
Triton X ◽  
Selective Accumulation ◽  
Cobalamin Absorption

The purpose of these studies was to determine whether gastric intrinsic factor and the ileal intrinsic factor receptor participate in the process of cobalamin absorption in the dog. Physicochemical analysis of gastrointestinal fluids and mucosal extracts obtained 3-5 h after cyano[57Co]-cobalamin was fed to dogs demonstrated that 1) all cyano-[57Co]cobalamin became bound to proteins during intraluminal transport; and 2) mucosal cyano[57Co]cobalamin in the extract of the ileal mucosa was bound to intrinsic factor, to intrinsic factor coupled to receptor protein, and to proteins with properties similar to R protein and transcobalamin II. A significant fraction of the cyano[57Co]cobalamin in the mucosal extract was membrane bound and, upon solubilization with Triton X-100, was found to contain immunoreactive intrinsic factor that, however, could no longer couple to the isolated receptor. The formation of the complex of cobalamin with intrinsic factor and the receptor protein and the selective accumulation of cobalamin in the ileum indicate that the intrinsic factor-mediated mechanism for absorption of this vitamin is active in the dog.

Genetic Evidence of an Accessory Activity Required Specifically for Cubilin Brush-Border Expression and Intrinsic Factor-Cobalamin Absorption

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3604-3606 ◽  
Author(s):  
Danbin Xu ◽  
Renata Kozyraki ◽  
Thomas C. Newman ◽  
John C. Fyfe
Keyword(s):  
Brush Border ◽  
Genetic Basis ◽  
Intrinsic Factor ◽  
Canine Model ◽  
Renal Tubules ◽  
Locus Heterogeneity ◽  
High Identity ◽  
Protein Reabsorption ◽  
Cobalamin Absorption ◽  
Cobalamin Malabsorption

Cubilin is a high molecular weight multiligand receptor that mediates intestinal absorption of intrinsic factor-cobalamin and selective protein reabsorption in renal tubules. The genetic basis of selective intestinal cobalamin malabsorption with proteinuria was investigated in a canine model closely resembling human Imerslund-Gräsbeck syndrome caused by cubilin mutations. CanineCUBN cDNA was cloned and sequenced, showing high identity with human and rat CUBN cDNAs. An intragenic CUBN marker was identified in the canine family and used to test the hypothesis of genetic linkage of the disease and CUBN loci. Linkage was rejected, indicating that the canine disorder resembling Imerslund-Gräsbeck syndrome is caused by defect of a gene product other than cubilin. These results imply that there may be locus heterogeneity among human kindreds with selective intestinal cobalamin malabsorption and proteinuria and that normal brush-border expression of cubilin requires the activity of an accessory protein.

Intestinal uptake and release of cobalamin complexed with rat intrinsic factor

1985 ◽  
Vol 248 (3) ◽  
pp. G326-G331 ◽  
Author(s):  
B. Seetharam ◽  
M. Presti ◽  
B. Frank ◽  
C. Tiruppathi ◽  
D. H. Alpers
Keyword(s):  
Brush Border ◽  
Brush Border Membrane ◽  
Intrinsic Factor ◽  
Acidic Environment ◽  
Organ Cultures ◽  
Intestinal Uptake ◽  
Cellular Compartment ◽  
Pancreatic Proteases ◽  
Small Intestinal ◽  
Uptake And Release

The mechanism of uptake of intrinsic factor (IF) and cobalamin (Cbl) by enterocytes and their subsequent fate have been uncertain. To examine this problem double-labeled IF X Cbl was added to small intestinal organ cultures. When 125I-IF X [57Co]Cbl was added to rabbit ileal explants, binding and internalization increased linearly for 24 h. After an 18-h chase with nonlabeled IF X Cbl, no 125I-IF returned to the cell surface. An amount of 35-45% of the internalized Cbl was found free, not bound to IF or any other protein. About 60% of both internalized ligands was bound to membranes but by a non-Ca2+-dependent bond, suggesting binding to a protein other than the brush-border receptor. Cobalamin was released from IF at pH 5.0 to the same degree (30%) as free Cbl was found inside the cell (35-45%). Neither pancreatic proteases nor ileal homogenates effected release of Cbl from IF. When cathepsins were added, the Cbl released was no greater than could be attributed to pH 5.0 alone. Chloroquine added to tissue explants did not alter the percentage of free intracellular Cbl. From these results we suggest that IF X Cbl is internalized and detached from the receptor within the enterocyte. The mechanism of release is not known but seems to require an acid pH (5.0). The Cbl is released in the mucosa, perhaps when the IF X Cbl complex enters a nonlysosomal cellular compartment with an acidic environment. There is no substantial recycling of IF to the brush-border membrane.

Lack of effect of alcohol on small intestinal binding of the vitamin B12 – intrinsic factor complex

1976 ◽  
Vol 54 (4) ◽  
pp. 469-476 ◽  
Author(s):  
J. Findlay ◽  
E. Sellers ◽  
G. Forstner
Keyword(s):  
Vitamin B12 ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Smooth Endoplasmic Reticulum ◽  
Intrinsic Factor ◽  
Binding Activity ◽  
Membrane Receptors ◽  
Time Period ◽  
Small Intestinal ◽  
And Control

Absorption of 57Co-labelled vitamin B12 – intrinsic factor (IF) complex and its binding to mucosal precipitate and brush border fractions of rat small intestine was studied in rats pair-fed with a liquid diet containing ethanol 5 g/100 ml, 35% of calories, or isocalorically substituted sucrose. IF was obtained from rats fasted for 18 h, and for each experiment the amount of vitamin B12 added was the minimum required to achieve maximum binding to IF. Rats fed alcohol exhibited hepatic steatosis, proliferation of smooth endoplasmic reticulum, and disordered mitochondria after 6 weeks on the diet, and absorption of vitamin B12, fed with IF by stomach tube, was reduced significantly. In contrast, binding of 57Co-labelled vitamin B12 – IF complex to mucosal precipitate and brush border fractions was never less than that of fractions from control rats at 4, 8 and 12 weeks on the alcohol diet. Furthermore, binding to the brush border was significantly greater in alcohol-fed rats at 12 weeks whether expressed per unit of β-naphthylamidase (EC 3.4.1.1) activity or per milligram of protein. Total mucosal sucrase (EC 5.2.1.26) and β-naphthylamidase were unchanged or slightly increased (β-naphthylamidase at 12 weeks) on the alcohol-containing diet indicating that total brush border membrane was not reduced. Total brush border binding activity was the same in alcohol-fed and control rats at each time period. These results indicate that malabsorption of vitamin B12 in rats fed alcohol cannot be due to decreased binding of the vitamin B12 – IF complex by brush border membrane receptors, or secondary to a net decrease in membrane receptors.

scholarly journals How I treat cobalamin (vitamin B12) deficiency

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2214-2221 ◽  
Author(s):  
Ralph Carmel
Keyword(s):  
Key Management ◽  
Intrinsic Factor ◽  
Vitamin B12 Deficiency ◽  
Cobalamin Deficiency ◽  
Recent Developments ◽  
B12 Deficiency ◽  
Management Principle ◽  
Underlying Disorder ◽  
Cobalamin Absorption

Abstract The challenges in medical management of cobalamin deficiency lie in attention to the unique pathophysiology that underlies cobalamin deficiency, more than in the mechanics of therapy. The central physiologic principles are that clinically important deficiency is more likely to occur (and progress) when intrinsic factor–driven absorption fails than when diet is poor and that most causes take years to produce clinically obvious deficiency. Transient defects have little clinical impact. The key management principle is the importance of follow-up, which also requires knowing how the deficiency arose. The virtues of these principles are not always fully appreciated. Recent developments have made diagnosis and management more difficult by diminishing the ability to determine cobalamin absorption status. Clinicians must also grapple with premature medicalization of isolated, mild biochemical changes that added many asymptomatic cases of still undetermined medical relevance to their caseload, often expanded by inflated cobalamin level criteria. The potential for misattribution of cobalamin-unrelated presentations to nongermane cobalamin and metabolite abnormalities has grown. Pathophysiologically based management requires systematic attention to each of its individual components: correctly diagnosing cobalamin deficiency, reversing it, defining its underlying cause, preventing relapse, managing the underlying disorder and its complications, and educating the patient.

Experience With Grant Writing: Where Do I Even Begin?

2010 ◽  
Vol 11 (1) ◽  
pp. 21-24
Author(s):  
Nicole M. Mancini
Keyword(s):  
Lessons Learned ◽  
Economic Situation ◽  
Grant Writing ◽  
Personal Journey ◽  
Know How ◽  
Daunting Task

Abstract At first, grant writing may look like a daunting task. You may ask yourself, “Is it really worth the time and effort?” With today's economic situation, teachers and therapists need ways to supplement their programs and grants provide such an opportunity. However, many of us do not know how to get started. After a few experiences and many lessons learned, I have come to enjoy researching and writing grants to supplement my students' learning. It is well worth the time and effort. This article provides information about a personal journey, lessons learned, and resources to get you started.

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