Reduced ileal expression of OSTalpha-OSTbeta in non-obese gallstone disease.
Cholelithiasis is a multifactorial process, and several mechanisms have been postulated. A decreased expression of the ileal apical sodium-dependent bile acid transporter (ASBT) and of the cytosolic ileal lipid binding protein (ILBP) was recently described in female non-obese patients. The role of the recently identified organic solute transporters alpha and beta (OSTalpha, OSTbeta) in gallstone pathogenesis remains unclear. Therefore, we performed analysis of OSTalpha-OSTbeta in gallstone patients according to body weight. Ileal mucosal biopsies were collected during routine colonoscopy from female gallstone carriers (n = 19) and controls (n = 34). OSTalpha-OSTbeta mRNA expression was measured using the LightCycler sequence detection system; protein was analyzed by immunohistochemistry and Western blot. The mRNA expression of OSTalpha-OSTbeta was significantly reduced (OSTalpha: 3.3-fold, P = 0.006; OSTbeta: 2.6-fold, P = 0.03) in normal-weight but not overweight gallstone carriers compared with controls. OSTalpha-OSTbeta protein levels also showed a reduction by 40-67%. The expression of OSTalpha-OSTbeta correlated positively with ASBT (r = 0.65, 0.58, respectively), ILBP (r = 0.77, 0.67), and the farnesoid X receptor (r = 0.58, 0.50). Fibroblast growth factor-19 showed a 2.8-fold reduction (P = 0.06), and liver receptor homolog-1 showed a 2-fold reduction (P = 0.04) in non-obese patients. In conclusion, an impaired function of all three ileal bile acid transporters may lead to low ileal bile acid reabsorption and an altered bile acid pool composition and therefore may contribute to the formation of gallstones in non-obese patients.
Renner
Olga
O
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology Stuttgart and University of Tübingen, Germany.
Harsch
Simone
S
Strohmeyer
André
A
Schimmel
Silke
S
Stange
Eduard F
EF
D000368:Aged; D004268:DNA-Binding Proteins / Q000502:physiology*; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000502:physiology*; D042882:Gallstones / Q000209:etiology / Q000503:physiopathology*; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007082:Ileum / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D050177:Overweight / Q000150:complications* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D027981:Symporters / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D004268:DNA-Binding Proteins; D050556:Fatty Acid-Binding Proteins; D005346:Fibroblast Growth Factors; D005768:Gastrointestinal Hormones; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human; C082631:NR5A2 protein, human; C476575:organic solute transporter alpha, human; C476577:SLC51B protein, human; C057275:fatty acid-binding protein 6; C071908:sodium-bile acid cotransporter