Exploring possible mechanisms for primary bile acid malabsorption: evidence for different regulation of ileal bile acid transporter transcripts in chronic diarrhoea.
OBJECTIVE
Chronic diarrhoea resulting from primary idiopathic bile acid malabsorption (IBAM) is common, but its aetiology is largely unknown. We investigated possible mechanisms, first looking for common sequence variations in the cytoplasmic ileal bile acid-binding protein (IBABP, gene symbol FABP6), and secondly, determining the expression of ileal mucosal transcripts for the apical sodium-linked bile acid transporter (ASBT), IBABP, the putative basolateral transporters, OSTalpha and OSTbeta, and regulatory factors.


METHODS
Genomic DNA was prepared from two cohorts of patients and two control groups; the promoter and exonic regions of FABP6 were sequenced. In intestinal biopsies, transcript expression was measured by quantitative real time-PCR, using ileum from 17 patients and 21 controls.


RESULTS
Sequence variations were identified in FABP6, but overall frequencies were similar in patients and controls. Transcripts of ASBT and IBABP, but not OSTalpha and OSTbeta, were expressed at higher levels in ileum than duodenum. The transcription factors farnesoid-X-receptor (FXR) and liver-receptor-homologue (LRH-1) were also more abundant in ileum, as was fibroblast growth factor 19 (FGF19), unlike short heterodimer partner (SHP), c-Fos, or CDX2. No significant differences in mean or median values were found between the groups for any of these transcripts. However, findings on regression analysis suggested that these transporters differ in their regulation, particularly in the relationships of CDX2, LRH-1 and FXR with OSTalpha.


CONCLUSIONS
Most cases of IBAM are unlikely to be caused by genetic variation in FABP6 or by major differences in transporter transcript expression. Our evidence indicates that other factors, such as regulation of expression of the basolateral bile acid transporter, should be considered as possible causes.
Balesaria
Sara
S
Gastroenterology Section, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK.
Pell
Robert J
RJ
Abbott
Lucy J
LJ
Tasleem
Ali
A
Chavele
Konstantia-Marie
KM
Barley
Natalie F
NF
Khair
Umma
U
Simon
Alex
A
Moriarty
Kieran J
KJ
Brydon
W Gordon
WG
Walters
Julian R F
JR
D000328:Adult; D000368:Aged; D001647:Bile Acids and Salts / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D003967:Diarrhea / Q000209:etiology / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000235:genetics; D005786:Gene Expression Regulation; D005787:Gene Frequency; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008286:Malabsorption Syndromes / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D014157:Transcription Factors / Q000378:metabolism
D001647:Bile Acids and Salts; D002352:Carrier Proteins; C117476:FGF19 protein, human; D050556:Fatty Acid-Binding Proteins; D005768:Gastrointestinal Hormones; D008562:Membrane Glycoproteins; D014157:Transcription Factors; C037643:bile acid binding proteins; C057275:fatty acid-binding protein 6; D005346:Fibroblast Growth Factors