Ileal mucosal bile acid absorption is increased in Cftr knockout mice

Stelzner, Matthias; Somasundaram, Siva G; Lee, Sum P.; Kuver, Rahul

doi:10.1186/1471-230x-1-10

Cited by 9 publications

(7 citation statements)

References 40 publications

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“…Bile acid malabsorption has also been reported in a SeHCAT retention analysis of CF patients (O'Brien et al 1993), although an in-vivo perfusion study of human ileum failed to detect any difference in taurocholate and glycocholate uptake between control and CF subjects (Thompson & Davidson 1988). The only other study to use transgenic CF mice to investigate ileal bile acid re-absorption in CF found that, in contrast to the results presented here, taurocholic acid uptake was enhanced in an everted sleeve preparation of CF ileum (Stelzner et al 2001). However, this group used a knockout mouse in which no CFTR is produced, while we have used mice with the ¢F508 mutation where aberrant CFTR is produced but, due to a trafficking defect, fails to reach its normal location at the luminal membrane of the enterocyte (Riordan 1993).…”

Section: Discussioncontrasting

confidence: 99%

Absorption of taurocholic acid by the ileum of normal and transgenic ΔF508 cystic fibrosis mice

Hardcastle

Harwood

Taylor

2004

Journal of Pharmacy and Pharmacology

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Changes in intestinal transport in cystic fibrosis (CF) include both defective Cl(-) secretion and alterations in absorption. This study focused on the effects of CF on the active re-absorption of bile acids in the ileum of normal and transgenic CF mice. Taurocholic acid absorption was monitored as changes in short-circuit current (SCC) in intact and stripped ileal sheets from normal (Swiss) and transgenic CF (Cftr(tm2Cam)) mice with the DeltaF508 mutation. Taurocholic acid uptake was measured directly in everted ileal sacs and in brush-border membrane vesicles (BBMVs) using radiolabelled bile acid. Taurocholic acid caused a biphasic increase in SCC in both intact and stripped ileal sheets from Swiss mice. The initial phase of the response was associated with active bile acid absorption as it was inhibited by a low mucosal Na(+) concentration, but unaffected by Cl(-)-free conditions, serosal furosemide or mucosal diphenylamine-2-carboxylic acid (DPC). The first phase was concentration-dependent and was reduced in the presence of other actively transported bile acids. Intact ileal sheets from wild-type Cftr(tm2Cam) mice also exhibited a biphasic SCC response to taurocholic acid, but in CF tissues the initial phase was reduced and the second phase was absent. Taurocholic acid was actively taken up by everted ileal sacs from Swiss mice. This process was inhibited by a low mucosal Na(+) concentration or the presence of other actively transported bile acids. A similar taurocholic acid uptake was observed in ileal sacs from wild-type mice, but in those from CF mice transport of the bile acid was significantly reduced. However, taurocholic acid uptake was similar in BBMVs from wildtype and CF ilea. Active absorption of taurocholic acid occurs in mouse ileum and this process is reduced in transgenic mouse models of CF with the DeltaF508 mutation. However, this difference cannot be detected in an isolated preparation of brush-border membranes.

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Section: Discussioncontrasting

confidence: 99%

Absorption of taurocholic acid by the ileum of normal and transgenic ΔF508 cystic fibrosis mice

Hardcastle

Harwood

Taylor

2004

Journal of Pharmacy and Pharmacology

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“…BA loss may also result from a primary cell defect in the active absorption of BA in the ileum. In vitro studies using brush border membrane vesicles from CF patients have shown that total ileal BA uptake is diminished [176,177]. Surprisingly, a study of Ileal Biliary Acid Transporter (IBAT) in CFTR knock-out mice shows a BA uptake rate four-fold that of wild-type mice [178].…”

Section: Intraluminal Abnormalitiesmentioning

confidence: 99%

Mechanisms of lipid malabsorption in Cystic Fibrosis: the impact of essential fatty acids deficiency

et al. 2005

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Transport mechanisms, whereby alimentary lipids are digested and packaged into small emulsion particles that enter intestinal cells to be translocated to the plasma in the form of chylomicrons, are impaired in cystic fibrosis. The purpose of this paper is to focus on defects that are related to intraluminal and intracellular events in this life-limiting genetic disorder. Specific evidence is presented to highlight the relationship between fat malabsorption and essential fatty acid deficiency commonly found in patients with cystic fibrosis that are often related to the genotype. Given the interdependency of pulmonary disease, pancreatic insufficiency and nutritional status, greater attention should be paid to the optimal correction of fat malabsorption and essential fatty acid deficiency in order to improve the quality of life and extend the life span of patients with cystic fibrosis.

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“…Other studies noticed that the inhibition of CFTR did not modify the activity of Na ϩ -dependent glucose transporter 1 (21). Furthermore, ileal bile acid transporter and taurocholate uptake were increased in cftr Ϫ/Ϫ mice (33). Overall, these data emphasize that the defect in intestinal lipid absorption in the present study is not specific and that the expression of proteins involved in other metabolic pathways is not modified.…”

Section: Discussionmentioning

confidence: 46%

Abnormal intracellular lipid processing contributes to fat malabsorption in cystic fibrosis patients

Peretti¹,

Roy²,

Drouin³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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A common feature of cystic fibrosis (CF) is the functional derangement of the exocrine pancreas, which affects output of pancreatic lipase. This condition results in severe dietary malabsorption due to the poor hydrolysis of triacylglycerol (TG) in the lumen of the small intestine. Despite the benefits of pancreatic enzyme supplements, patients with CF present with persistent intestinal fat malabsorption. The aim of the present investigation was to determine whether defects in the intracellular phase of lipid transport occur in this pathophysiology in addition to the known disturbed digestive processes. Our hypothesis was tested by incubating intestinal biopsies from six CF and six healthy subjects with radiolabeled lipid and protein precursors. Lipid esterification and secretion were markedly decreased by 22-31% and 38-42%, respectively, in CF samples, as noted by the low incorporation of [(14)C]palmitic acid into TGs, phospholipids, and cholesteryl esters in patients' duodenal explants and culture media compared with controls (100%). Accordingly, the output of TG-rich lipoproteins was substantially reduced (P < 0.05), and a similar trend was observed for high-density lipoproteins. Because intestinal lipoprotein assembly/secretion shows an absolute requirement for apolipoprotein (apo) B-48, radioactive labeling experiments were performed; these experiments demonstrated a significantly (P < 0.05) diminished synthesis of apoB-48 (40%) and apoA-I (30%). Given the critical role of microsomal triglyceride transfer protein in the formation of apoB-containing lipoproteins, its activity was determined and not found to be altered in CF intestinal tissue. Together, these results suggest that CF malabsorption may also be caused by defects in mucosal mechanisms leading to abnormal lipoprotein delivery into the blood circulation.

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Ileal mucosal bile acid absorption is increased in Cftr knockout mice

Cited by 9 publications

References 40 publications

Absorption of taurocholic acid by the ileum of normal and transgenic ΔF508 cystic fibrosis mice

Absorption of taurocholic acid by the ileum of normal and transgenic ΔF508 cystic fibrosis mice

Mechanisms of lipid malabsorption in Cystic Fibrosis: the impact of essential fatty acids deficiency

Abnormal intracellular lipid processing contributes to fat malabsorption in cystic fibrosis patients

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