ASBT activation may hold key to IBD

The apical sodium-dependent ileal bile acid transporter gene, ASBT, is activated by glucocorticoids, study findings indicate, offering a novel link between the pathways that govern bile acid homeostasis, lipid metabolism, and inflammation control. As ASBT is induced by glucocorticoids in rats, so Gerd Kullak (University Hospital, Zurich, Switzerland) and collaborators investigated whether a similar mechanism is apparent in humans.

The apical sodium-dependent ileal bile acid transporter gene, ASBT, is activated by glucocorticoids, study findings indicate, offering a novel link between the pathways that govern bile acid homeostasis, lipid metabolism, and inflammation control. As ASBT is induced by glucocorticoids in rats, so Gerd Kullak (University Hospital, Zurich, Switzerland) and collaborators investigated whether a similar mechanism is apparent in humans. Western blot analysis of ileal biopsies showed that ASBT expression was lower in patients with Crohn’s disease than in healthy male volunteers (ASBT/villin ratio 1.27 vs 0.88, p=0.01). “ASBT expression was not correlated with local inflammation,” the authors comment. Volunteers then took the synthetic corticosteroid, budesonide, for 21 days. Repeat biopsy revealed that ASBT protein expression had increased 1.34-fold over baseline (p<0.05), whereas expression of the peptide transporter-1 was unaffected. "Reporter constructs of the human ASBT promoter were activated 15 to 20-fold by coexpression of the glucocorticoid receptor and exposure to the ligands dexamethasone or budesonide," Kullak et al report in the journal Gut. Furthermore, two glucocorticoid response elements in the ASBT promoter conferred inducibility by the glucocorticoid receptor and dexamethasone in a heterologous promoter context and were shown to bind the glucocorticoid receptor in mobility shift assays. "Our data show conclusively that the ASBT gene binds and is transactivated by the glucocorticoid receptor, thereby adding an important target gene to the spectrum of glucocorticoid-regulated genes in the human intestine," Kullak's team concludes. Their findings have major implications in view of the central role of glucocorticoids in the treatment of inflammatory bowel disorders. "The beneficial effects could be related in part to increased ASBT expression and consequently reduced spillover of bile acids into the colon," they suggest. (Source Gut 2004; 53: 78-84)