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)

Folate plays a critical role in maintaining normal metabolic, energy, differentiation and growth status of all mammalian cells. The disturbances in body folate homeostasis such as intestinal malabsorption in alcoholism are well-known contributor to folate deficiency associated disorders. The study was sought to delineate the kinetic features of folate transport in intestinal absorptive epithelium that could highlight insights of malabsorption during alcoholism. We studied [(3)H]-folic acid transport in intestinal brush border membrane (BBM) after 3 months of ethanol administration at 1 g/kg body weight/day to rats. The results showed that the folate transport exhibited saturable kinetics and was pH, Na(+), temperature, divalent cation sensitive, besides -SH group(s) was/were found important in the folate transport system to be efficiently operative. Importantly, the decreased intestinal BBM folate transport in chronic alcoholism was associated with increased K (m) and decreased V (max) during alcoholism. In addition, S-S group status of the transporter and presence of Na(+ )at the absorptive site seems to be perturbed during ethanol ingestion. However, H(+)/folate(-) coupled transport provided the driving force for transport as pH optimum in acidic range was not altered during alcoholism. The inhibition constants of methotrexate and unlabelled folic acid revealed that the two analogues are handled differently by the folate transport system. In addition, the low activity of folate transport system during chronic ethanol exposure was associated with low RBC folate levels. Overall, these findings suggest that the deregulated folate transport kinetics might contribute to intestinal folate malabsorption in alcoholism.
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PMID:Evaluation of the kinetic properties of the folate transport system in intestinal absorptive epithelium during experimental ethanol ingestion. 1753 Jan 84

Alcoholic liver disease (ALD) evolves through various stages, and malnutrition correlates with the severity of ALD. Poor nutrition is caused both by the substitution of calories from alcohol for calories from food and by the malabsorption and maldigestion of various nutrients attributed to ALD. The only established therapy for ALD consists of abstinence from alcohol. Sufficient nutritional repletion coupled with appropriate supportive treatment modalities may be effective in reducing complications associated with ALD---particularly infection. Nutrition makes a significant positive contribution in the treatment of ALD, especially in selected malnourished patients.
Alcohol Res Health 2006
PMID:The role of nutritional therapy in alcoholic liver disease. 1771 10

The folic acid transport across epithelial cell membrane of the intestine is an essential step for its absorption, conservation, and homeostasis in the body. In this study, we sought to examine the kinetics of binding to intestinal brush border membrane (BBM) considering intestinal malabsorption as the major contributing factor to alcohol-induced folate deficiency. Male Wistar rats were fed 1g/kg body weight/day ethanol (20% solution) orally for 3 months. We studied [(3)H]-folic acid binding to the intestinal BBM and acidic pH-dependent binding was observed to be associated with reduced maximal binding (B(max)) in chronic ethanol-fed group. However, under such conditions, there was no significant effect of ethanol ingestion on K(d) and pH optimum of the binding process. Increasing the osmolarity at pH 5.5 had no effect on the binding of folate to BBM, thus confirming that the observed changes in B(max) values were due to site-specific binding to the extravesicular sites. Importantly, ethanol ingestion disturbs the S-S status at the binding site besides interfering with the Na(+) and divalent cation dependency of the binding process. These results highlight the possible mechanism of folate malabsorption at primary absorptive site during alcoholism.
Alcohol 2007 Sep
PMID:Long-term alcohol ingestion alters the folate-binding kinetics in intestinal brush border membrane in experimental alcoholism. 1793 12

Folate plays a critical role in maintaining normal metabolic, energy, differentiation and growth status of all mammalian cells. The intestinal folate uptake is tightly and diversely regulated, and disturbances in folate homeostasis are observed in alcoholism, attributable, in part, to intestinal malabsorption of folate. The aim of this study was to delineate the regulatory mechanisms of folate transport in intestinal absorptive epithelia in order to obtain insights into folate malabsorption in a rat model of alcoholism. The rats were fed 1 g.kg(-1) body weight of ethanol daily for 3 months. A reduced uptake of [(3)H]folic acid in intestinal brush border membrane was observed over the course of ethanol administration for 3 months. Folate transport exhibited saturable kinetics and the decreased intestinal brush border membrane folate transport in chronic alcoholism was associated with an increased K(m) value and a low V(max) value. Importantly, the lower intestinal [(3)H]folic acid uptake in ethanol-fed rats was observed in all cell fractions corresponding to villus tip, mid-villus and crypt base. RT-PCR analysis for reduced folate carrier, the major folate transporter, revealed that reduced folate carrier mRNA levels were decreased in jejunal tissue derived from ethanol-fed rats. Parallel changes were observed in reduced folate carrier protein levels in brush border membrane along the entire crypt-villus axis. In addition, immunohistochemical staining for reduced folate carrier protein showed that, in alcoholic conditions, deranged reduced folate carrier localization was observed along the entire crypt-villus axis, with a more prominent effect in differentiating crypt base stem cells. These changes in functional activity of the membrane transport system were not caused by a general loss of intestinal architecture, and hence can be attributed to the specific effect of ethanol ingestion on the folate transport system. The low folate uptake activity observed in ethanol-fed rats was found to be associated with decreased serum and red blood cell folate levels, which might explain the observed jejunal genomic hypomethylation. These findings offer possible mechanistic insights into folate malabsorption during alcoholism.
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PMID:Down-regulation of reduced folate carrier may result in folate malabsorption across intestinal brush border membrane during experimental alcoholism. 1800 57

Folate is an essential cofactor for normal cellular proliferation and tissue regeneration. Alcohol-associated folate deficiency is common, primarily due to intestinal malabsorption, the mechanism of which needs attention. The aim of the present study was to evaluate the regulatory events of folate transport in experimental alcohol ingestion. For this, male Wistar rats were fed 1 g/kg body weight/day ethanol (20% solution) orally for 3 months and folate transport was studied in isolated intestinal epithelial cells across the crypt-villus axis. The role of different signaling pathways in folate transport regulation was evaluated independently to that of reduced folate carrier (RFC) expression. The results showed that differentiated cells of villus possess high folate uptake activity as compared to mid villus and crypt base cells. During chronic ethanol ingestion, decrease in transport was observed all along the crypt-villus axis but was more pronounced at proliferating crypt base stem cells. Studying the effect of modulators of signaling pathways revealed the folate transport system to be under the regulation of cAMP-dependent protein kinase A (PKA), the activity of which was observed to decrease upon alcohol ingestion. In addition, protein kinase C might have a role in folate transport regulation during alcoholic conditions. The deregulation in the folate transport system was associated with a decrease in RFC expression, which may result in lower transport efficiency observed at absorptive surface in alcohol-fed rats. The study highlights the role that perturbed regulatory pathways and RFC expression play in the decreased folate transport at brush border surface during alcohol ingestion.
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PMID:Role of signaling pathways in the regulation of folate transport in ethanol-fed rats. 1860 15

Alcohol damages every organ and system in the body. The most important effects from a clinical point of view relate to diseases of the circulatory, nervous and hepato-gastrointestinal systems. In the digestive tract the effects range from increased intestinal transit time and gastrophaties, leading to classical early morning nausea and diarrhea, through to significant malabsorption and chronic pancreatitis. In this review the mechanisms of alcoholic damage have been evaluated with particular reference to alcoholic liver disease (ALD). In particular, the natural history, the influence due to host genetic susceptibility and due to cofactors (i.e. hepatitis C virus), the clinical features and the hepatocarcinogenesis mechanisms have been evaluated. Finally, a possible role of abstinence in association with pharmacological therapy in the course of steatohepatitis has also been evaluated.
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PMID:Alcoholic diseases in hepato-gastroenterology: a point of view. 1861 69

The process of folate transport regulation across biological membranes is of considerable interest because of its ultimate role in providing one-carbon moieties for key cellular metabolic reactions and exogenous requirement of the vitamin in mammals. Although, intestinal folate malabsorption is established phenomena in alcoholism; however, there is no knowledge regarding the mechanism of folate exit across intestinal basolateral membrane (BLM) to circulation during alcohol associated malabsorption. In the present study, male Wistar rats were fed 1 g/kg body weight/day ethanol (20% solution) orally for 3 months and regulatory characteristics of folate transport at BLM surface were evaluated. The folate transport was found to be carrier mediated, saturable, with pH optima at 7.0, besides exhibiting Na(+) independence. The chronic alcohol ingestion resulted in alteration of transport kinetics, shifting the process to K(+) dependent one besides affecting the status of S--S linkage of the transport system. Importantly, chronic ethanol ingestion reduced the folate exit across the BLM by decreasing the affinity of transporter (high K(m)) for substrate and by decreasing the number of transporter molecules (low V(max)) on the surface. The decreased basolateral transport activity was associated with down-regulation of the reduced folate carrier (RFC) which resulted in decreased RFC protein levels in BLM in rat model of alcoholism. The study suggests that during alcohol ingestion, RFC mediated deregulated folate transport across BLM also attributes to folate malabsorption.
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PMID:Low folate transport across intestinal basolateral surface is associated with down-regulation of reduced folate carrier in in vivo model of folate malabsorption. 1924 12

Chronic excessive alcohol administration has been reported to be associated with diastolic dysfunction. Parvalbumin (PV) is a calcium-binding protein present in cardiac myocytes and involved in mediating relaxation. Therefore, alteration of PV levels may affect relaxation in cardiac myocytes. This study investigated the effects of alcohol administration on the levels of PV in the rat heart. Male Wistar rats weighing 200-250 g were divided into 2 groups: control (C) and alcohol-treated groups. The control group was provided with distilled water and the alcohol groups were provided with either a low dose (LD, 2g/kg) or high dose of ethanol (HD, 5 g/kg) once daily for 21 days, 3 months or 6 months. The PV levels in the ventricles were investigated by immunohistochemistry and Western blot analysis. In the 21-day ethanol-treated groups, parvalbumin immunoreactivity (PV-ir) and protein levels were not different when compared to the C, LD and HD groups. In the 3-month ethanol-treated groups, PV-ir and PV protein levels were decreased in both the LD and HD groups compared to that of the control group. In the 6-month ethanol-treated groups, PV-ir and PV protein levels decreased significantly in both the LD and HD groups (P<0.05). This indicates that short-term ethanol treatment may not affect PV levels, whereas, long-term ethanol treatment clearly reduced PV levels. The decrease of PV was predominantly due to the direct toxic effects of alcohol rather than malabsorption caused by pathological changes in the duodenum and liver. The toxic effects of alcohol leading to a reduction of PV levels may lead to diastolic impairment.
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PMID:Effects of alcohol on the levels of parvalbumin in rat hearts. 1928 40

Folates are members of the B-class of vitamins, which are required for the synthesis of purines and pyrimidines, and for the methylation of essential biological substances, including phospholipids, DNA, and neurotransmitters. Folates cannot be synthesized de novo by mammals; hence, an efficient intestinal absorption process is required. Intestinal folate transport is carrier-mediated, pH-dependent and electroneutral, with similar affinity for oxidized and reduced folic acid derivatives. The various transporters, i.e. reduced folate carrier, proton-coupled folate transporter, folate-binding protein, and organic anion transporters, are involved in the folate transport process in various tissues. Any impairment in uptake of folate can lead to a state of folate deficiency, the most prevalent vitamin deficiency in world, affecting 10% of the population in the USA. Such impairments in folate transport occur in a variety of conditions, including chronic use of ethanol, some inborn hereditary disorders, and certain diseases. Among these, ethanol ingestion has been the major contributor to folate deficiency. Ethanol-associated folate deficiency can develop because of dietary inadequacy, intestinal malabsorption, altered hepatobiliary metabolism, enhanced colonic metabolism, and increased renal excretion. Ethanol reduces the intestinal and renal uptake of folate by altering the binding and transport kinetics of folate transport systems. Also, ethanol reduces the expression of folate transporters in both intestine and kidney, and this might be a contributing factor for folate malabsorption, leading to folate deficiency. The maintenance of intracellular folate homeostasis is essential for the one-carbon transfer reactions necessary for DNA synthesis and biological methylation reactions. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. Ethanol, a toxin that is consumed regularly, has been found to affect the methylation of DNA. In addition to its effect on DNA methylation due to folate deficiency, ethanol could directly exert its effect through its interaction with one-carbon metabolism, impairment of methyl group synthesis, and affecting the enzymes regulating the synthesis of S-adenosylmethionine, the primary methyl group donor for most biological methylation reactions. Thus, ethanol plays an important role in the pathogenesis of several diseases through its potential ability to modulate the methylation of biological molecules. This review discusses the underlying mechanism of folate malabsorption in alcoholism, the mechanism of methylation-associated silencing of genes, and how the interaction between ethanol and folate deficiency affects the methylation of genes, thereby modulating epigenome stability and the risk of cancer.
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PMID:New perspectives on folate transport in relation to alcoholism-induced folate malabsorption--association with epigenome stability and cancer development. 1929 60

Anemia of diverse etiology is a common complication of chronic liver diseases. The causes of anemia include acute or chronic gastrointestinal hemorrhage, and hypersplenism secondary to portal hypertension. Severe hepatocellular disease predisposes to hemorrhage because of impaired blood coagulation caused by deficiency of blood coagulation factors synthesized by hepatocytes, and/or thrombocytopenia. Aplastic anemia, which is characterized by pancytopenia and hypocellular bone marrow, may follow the development of hepatitis. Its presentation includes progressive anemia and hemorrhagic manifestations. Hematological complications of combination therapy for chronic viral hepatitis include clinically significant anemia, secondary to treatment with ribavirin and/or interferon. Ribavirin-induced hemolysis can be reversed by reducing the dose of the drug or discontinuing it altogether. Interferons may contribute to anemia by inducing bone marrow suppression. Alcohol ingestion is implicated in the pathogenesis of chronic liver disease and may contribute to associated anemia. In patients with chronic liver disease, anemia may be exacerbated by deficiency of folic acid and/or vitamin B12 that can occur secondary to inadequate dietary intake or malabsorption.
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PMID:Spectrum of anemia associated with chronic liver disease. 1978 28


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