Liver X receptor activation inhibits SGLT2-mediated glucose transport in human renal proximal tubular cells

Abstract

Liver X receptors (LXRs) are members of a nuclear receptor family consisting of two isoforms, LXR-α and LXR-β. They play a major role in energy metabolism including lipid and glucose metabolism. Recent studies reported LXRs regulate plasma glucose although the mechanism is still uncertain. The present study investigated whether LXR activation regulates sodium glucose cotransporter2 (SGLT2) in human renal proximal tubular cells. LXR agonists, T0901317 and GW3965, inhibited SGLT2-mediated glucose uptake in concentration-dependent manners. The effect of T0901317 and GW3965 was attenuated by a LXR antagonist, fenofibrate. Activation of retinoid X receptor (RXR) agonist, bexarotene, potentiates the inhibitory effect of these ligands. Thus, the inhibitory effect of LXR agonists on SGLT2 was mediated and facilitated by LXR and RXR activation, respectively. In addition, the inhibitory effect of LXR agonists was not mediated by cytotoxicity. Exposing HK-2 cells, renal proximal tubular cell line, to LXR agonists significantly reduced the maximal transport rate (J_max) of SGLT2 without any effect on transporter affinity. Western blot analysis revealed LXR activation significantly decreased protein expression of SGLT2 with no change in mRNA level. In addition, LXR activation inhibited canagliflozin-sensitive short-circuits current which represents SGLT2-mediated glucose transport in polarized human renal proximal tubular cell monolayer. Furthermore, LXR activation inhibited transport function of SGLT2 in hyperglycemic conditions. As such, this study represents the evidence of LXR activation's inhibitory effect on glucose transport in human renal proximal tubular cells.

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