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Background. The global growing burden of obesity and type 2 diabetes mellitus is widely recognized as one of the most challenging threats to public health. Bariatric surgery represents a potentially useful strategy for management of diabetes and obesity. FXR is a bile acid activated receptors expressed in entero-hepatic tissues.
Aims.Here we have investigated whether bariatric surgery activates liver and intestinal bile acids activated receptors and how these receptor regulate metabolic adaptation to surgery.
Methods.Wistar rats were followed for 7 months after Ileal interposition (IT) or sham operation. In the last week animals were challenged with CDCA, 10 mg/kg, a FXR ligand.
Results.
IT selectively increases intestinal expression/activity of FXR and liver X receptor (LXR), as demonstrated by increasing expression of theirs target genes in the intestine including FGF-15 and ABCG5/8, respectively. In contrast, IT selectively repressed FXR and LXR activity in the liver resulting in a robust reduction of the expression of genes involved in liver bile acids synthesis (CYP7A1) and uptake and secretion (NTCP, MRP2, MRP3, OSTα/β) ultimately leading to reduced bile acid concentrations in the blood. In addition, IT repressed the liver expression of neoglucogenetic (PECK) and lipogenetic (FAS, SREBP1c) genes. IT enhanced FGF-15 mRNA expression in the intestine and this effect was further enhanced by CDCA (Figure). Activation of intestinal FXR associates with an improvement of OGTT and with a reduction of glucose plasma levels.
Conclusions.These findings provide a mechanistic explanation to the metabolic effects exerted by bariatric surgery and provide a model for investigating the effect of selective activation of intestinal FXR.