Liver X Receptor Beta Regulates Bile Volume And The Expression Of Aquaporins And Cystic Fibrosis Transmembrane Conductance Regulator In The Gallbladder

The gallbladder is considered an important organ in maintaining digestive and metabolic homeostasis. Given that therapeutic options for gallbladder diseases are often limited to cholecystectomy, understanding gallbladder pathophysiology is essential in developing novel therapeutic strategies. Since liver X receptor beta (LXR beta), an oxysterol-activated transcription factor, is strongly expressed in gallbladder cholangiocytes, the aim was to investigate LXR beta physiological function in the gallbladder. Thus, we studied the gallbladders of WT and LXR beta(-/-) male mice using immunohistochemistry, electron microscopy, qRT-PCR, bile duct cannulation, bile and blood biochemistry, and duodenal pH measurements. LXR beta(-/-) mice presented a large gallbladder bile volume with high duodenal mRNA levels of the vasoactive intestinal polypeptide (VIP), a strong mediator of gallbladder relaxation. LXR beta(-/-) gallbladders showed low mRNA and protein expression of Aquaporin-1, Aquaporin-8, and cystic fibrosis transmembrane conductance regulator (CFTR). A cystic fibrosis-resembling phenotype was evident in the liver showing high serum cholestatic markers and the presence of reactive cholangiocytes. For LXR beta being a transcription factor, we identified eight putative binding sites of LXR on the promoter and enhancer of the Cftr gene, suggesting Cftr as a novel LXR beta regulated gene. In conclusion, LXR beta was recognized as a regulator of gallbladder bile volume through multiple mechanisms involving CFTR and aquaporins.NEW & NOTEWORTHY This report reveals a novel and specific role of the nuclear receptor liver X receptor beta (LXR beta) in controlling biliary tree pathophysiology. LXR beta(-/-) mice have high gallbladder bile volume and are affected by a cholangiopathy that resembles cystic fibrosis. We found LXR beta to regulate the expression of both aquaporins water channels and the cystic fibrosis transmembrane conductance regulator. This opens a new field in biliary tree pathophysiology, enlightening a possible transcription factor controlling CFTR expression.