Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024523 (malabsorption)
 7,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of the high prevalence of metabolic bone disease in older persons, we investigated the possibility of impaired intestinal absorptive capacity for vitamin D3 in aging animals. Using a single-pass technique, we measured vitamin D absorption and mucosal accumulation in male rats 9 to 101 weeks of age. Intestinal length, water absorption, and vitamin D3 intestinal tissue concentration remained constant after 41 weeks of age. Vitamin D3 absorption increased from 1209 pmol/100 cm/hr at 9 weeks of age to 2114 pmol/100 cm/hr at 41 weeks of age and remained relatively constant thereafter. Because vitamin D3 absorption rate is partly regulated by the dimensions of the unstirred water layer, we assessed the dimensions of the UWL of our aging animals. As the animals aged, the surface area of the UWL increased from 197 to 316 cm2/100 cm, and its resistance decreased from 1.2 to 0.7 min/cm3/100 cm by 41 weeks of age and remained stable thereafter. Inasmuch as the UWL is a major regulatory step in the absorption of vitamin D, its constant dimensions after 41 weeks of age explain the normal absorption of vitamin D3 observed in our aging animals. If these findings are found to be true in humans as well, they would argue against the possibility of vitamin D3 malabsorption as a cause of metabolic bone disease seen in aging individuals.
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PMID:Influence of aging on vitamin D absorption and unstirred water layer dimensions in the rat. 632 19

Only in the duodenum and in the colon calcium is absorbed by a cellular 1,25 alpha-Vitamin D3-dependent transport mechanism. Calcium absorption is highest in the proximal large intestine, about ten times higher than in the duodenum or in the descending colon. 1,25 alpha-Vitamin D3 stimulates calcium transport by genomic (slow effect: synthesis of cytosolic calcium binding protein CabP and basolateral Ca-ATPase) and non-genomic action (rapid effect: transcaltachyia, liponomic effect at the brush border membrane). CabP-dependent translocation across the cytosol is thought to be rate limiting step of cellular calcium transport. However, only about 50% of calcium absorption is cellular mediated but the same amount of calcium convectively is absorbed by transepithelial water flow across the paracellular pathway (solvent drag effect). 1,25 alpha-Vitamin D3 not only activates cellular calcium absorption but also increases paracellular permeability for calcium by an unknown mechanism. However, essential steps in the cascade from the interaction of 1,25 alpha-Vitamin D3 with the specific receptor over the regulation of the synthesis of calcium binding and transporting proteins to the induction of cellular calcium transport are not as yet clearly understood. The exact feedback mechanism of synchronized calcium transport across the distinct subcellular compartments seems also to be resolved. Cellular calcium transport is not found in the jejunum or in the ileum, what can be explained by the absence of specific 1,25 alpha-Vitamin D3-dependent carrier systems in these segments. On the other hand calcium is secreted across the jejunum and ileum by an anomalous solvent drag effect. Hence, intestinal calcium metabolism seems to underlie an eneteroenteral circuit: 1,25 alpha-Vitamin D3-controlled cellular calcium absorption across the duodenum is followed by paracellular calcium secretion across the jejunum and ileum. The carrier in the proximal colon which works at the optimal level already under normal nutritional condition could be of physiological importance for the reclamation of unabsorbed dietary calcium and for the reabsorption of calcium that is secreted across the distal small intestine. Under certain pathophysiological conditions, i.e. malabsorption in proximal segments or malnutrition, calcium in addition may be conserved by the 1,25 alpha-Vitamin D3-sensitive carrier in the descending colon.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[New findings on the mechanism and regulation of intestinal calcium transport]. 780 57

Vitamin D signaling is dependent on the availability and turnover of the active Vitamin D receptor (VDR) ligand 1,25-dihydroxycholecalciferol and on the efficiency of VDR transactivation. Activating and inactivating secosteroid metabolizing p450 enzymes, e.g. 25-hydroxylases, 1alpha-hydroxylase and 24-hydroxylase, are responsible for ligand availability on the basis of substrate production in the skin and of nutritional intake of precursors. Net availability of active hormone depends on the delivery of substrate and the balance of activating and inactivating enzymes. 1Alpha-hydroxylase is the critical activating enzyme. It is expressed in the kidney for systemic supply and in target tissues for local secosteroid activation. It is upregulated in the kidney by low calcium intake and parathyroid hormone, downregulated by phosphatonins and proinflammatory signal transduction. Transactivation of VDR depends on the correct molecule structure, effective nuclear translocation and the presence of the unliganded heterodimer partner retinoid X-receptor (RXR) and other nuclear cofactors. Rapid Vitamin D-dependent membrane associated effects and consecutive second messenger activation exert an own pattern of gene regulation. A membrane receptor for these effects is hypothesized but not yet identified. Rickets is the long known clinical syndrome of impaired Vitamin D signaling due to Vitamin D3 deficiency. It can be caused by inherited defects of the cascade, nutritional deficits, lack of sunlight exposure, malabsorption and underlying diseases like chronic inflammation. It has been shown during the last decades that many modifiers of Vitamin D signaling are targets of disease in terms of inherited and acquired syndromes and that Vitamin D signaling is modulated at multiple levels and is more complex than mere mechanistic ligand/receptor/DNA interaction.
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PMID:Vitamin D signaling is modulated on multiple levels in health and disease. 1640 53

Vitamin D3 is synthesized in the skin during summer under the influence of ultraviolet light of the sun, or it is obtained from food, especially fatty fish. After hydroxylation in the liver into 25-hydroxyvitamin D (25(OH)D) and kidney into 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite can enter the cell, bind to the vitamin D-receptor and subsequently to a responsive gene such as that of calcium binding protein. After transcription and translation the protein is formed, e.g. osteocalcin or calcium binding protein. The calcium binding protein mediates calcium absorption from the gut. The production of 1,25(OH)2D is stimulated by parathyroid hormone (PTH) and decreased by calcium. Risk factors for vitamin D deficiency are premature birth, skin pigmentation, low sunshine exposure, obesity, malabsorption and advanced age. Risk groups are immigrants and the elderly. Vitamin D status is dependent upon sunshine exposure but within Europe, serum 25(OH)D levels are higher in Northern than in Southern European countries. Severe vitamin D deficiency causes rickets or osteomalacia, where the new bone, the osteoid, is not mineralized. Less severe vitamin D deficiency causes an increase of serum PTH leading to bone resorption, osteoporosis and fractures. A negative relationship exists between serum 25(OH)D and serum PTH. The threshold of serum 25(OH)D, where serum PTH starts to rise is about 75nmol/l according to most surveys. Vitamin D supplementation to vitamin D-deficient elderly suppresses serum PTH, increases bone mineral density and may decrease fracture incidence especially in nursing home residents. The effects of 1,25(OH)2D and the vitamin D receptor have been investigated in patients with genetic defects of vitamin D metabolism and in knock-out mouse models. These experiments have demonstrated that for active calcium absorption, longitudinal bone growth and the activity of osteoblasts and osteoclasts both 1,25(OH)2D and the vitamin D receptor are essential. On the other side, bone mineralization can occur by high ambient calcium concentration, so by high doses of oral calcium or calcium infusion. The active metabolite 1,25(OH)2D has its effects through the vitamin D receptor leading to gene expression, e.g. the calcium binding protein or osteocalcin or through a plasma membrane receptor and second messengers such as cyclic AMP. The latter responses are very rapid and include the effects on the pancreas, vascular smooth muscle and monocytes. Muscle cells contain vitamin D receptor and several studies have demonstrated that serum 25(OH)D is related to physical performance. The active metabolite 1,25(OH)2D has an antiproliferative effect and downregulates inflammatory markers. Extrarenal synthesis of 1,25(OH)2D occurs under the influence of cytokines and is important for the paracrine regulation of cell differentiation and function. This may explain that vitamin D deficiency can play a role in the pathogenesis of auto-immune diseases such as multiple sclerosis and diabetes type 1, and cancer. In conclusion, the active metabolite 1,25(OH)2D has pleiotropic effects through the vitamin D receptor and vitamin D responsive elements of many genes and on the other side rapid non-genomic effects through a membrane receptor and second messengers. Active calcium absorption from the gut depends on adequate formation of 1,25(OH)2D and an intact vitamin D receptor. Bone mineralization mainly depends on ambient calcium concentration. Vitamin D metabolites may play a role in the prevention of auto-immune disease and cancer.
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PMID:Vitamin D physiology. 1656 71

Mounting evidence correlate vitamin D3 (cholecalciferol) supplementation or higher serum levels of vitamin D (25(OH)D) with a lower risk of developing multiple sclerosis (MS), reduced relapse rate, slower progression or fewer new brain lesions. We present here the case of a woman who was diagnosed with MS in 1990. From 1980 to 2000, her ability to walk decreased from ~20 to 1 km per day. Since January 2001, a vitamin D3 supplement was ingested daily. The starting dose was 20 mcg (800 IU)/day and escalated to 100 mcg (4000 IU)/day in September 2004 and then to 150 mcg (6000 IU)/day in December 2005. Vitamin D3 intake reduced muscular pain and improved ambulation from 1 (February 2000) to 14 km/day (February 2008). Vitamin D intake over 10 years caused no adverse effects: no hypercalcaemia, nephrolithiasis or hypercalciuria were observed. Bowel problems in MS may need to be addressed as they can cause malabsorption including calcium, which may increase serum PTH and 1,25(OH)2D levels, as well as bone loss. We suggest that periodic assessment of vitamin D3, calcium and magnesium intake, bowel problems and the measurement of serum 25(OH)D, PTH, Ca levels, UCa/Cr and bone health become part of the integral management of persons with MS.
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PMID:Effect of high-dose vitamin D3 intake on ambulation, muscular pain and bone mineral density in a woman with multiple sclerosis: a 10-year longitudinal case report. 2320 62