Liver X Receptor Activation Inhibits Intestinal Phosphate Transport

Renal Pi reabsorption has been considered the main mechanism controlling Pi homeostasis. However, recently small intestine Pi absorption has emerged as a putative pharmacological target for the control of hyperphosphatemia, especially important in the setting of chronic kidney disease. We have recently reported that activation of Liver X Receptor (LXR) with LXR agonists leads to a decreased serum Pi concentration and increased urinary Pi excretion. In parallel, these changes were associated with the decrease of renal and intestinal NaPi transporters expression. To investigate the potential mechanisms behind this regulation we used two transgenic mouse models expressing: 1) constitutively active form of the LXRα fused with the activation domain of VP16 under LXRα endogenous promoter (VP16‐LXRα Tg); 2) enterocyte‐specific LXRα under villin promoter (villin VP16‐LXRα Tg). VP16‐LXRα Tg and villin VP16‐LXRα Tg mice showed reduced sodium dependent Pi uptake in the brush border membrane (BBM) of enterocytes. This was accompanied by reduction of NaPi2b protein abundance in the BBM and also reduced ileum NaPi‐2b mRNA level. Our results show that the effects of enterocyte‐specific activation of LXR are independent of systemic influences and also highlight importance of the intestine in Pi homeostasis regulation. However, the putative mechanisms of LXR effects on Pi transport remain to be elucidated Supported by NIH