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

Abstract

© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society New Findings: What is the central question of this study? The liver X receptor (LXR) has been reported to regulate several membrane transporters. It is imperative to investigate whether LXR activation regulates SGLT2-mediated glucose transport in human renal proximal tubular cells. What is the main finding and its importance? Liver X receptor activation inhibits SGLT2 transport function in normal and high-glucose conditions via reduction of SGLT2 protein expression. Liver X receptors (LXRs) are members of a nuclear receptor family consisting of two isoforms, LXRα and LXRβ. They play a major role in energy metabolism, including lipid and glucose metabolism. Recent studies reported that 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 a concentration-dependent manner. The effect of T0901317 and GW3965 was attenuated by a LXR antagonist, fenofibrate. Activation of the 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, a renal proximal tubular cell line, to LXR agonists significantly reduced the maximal transport rate of SGLT2 without any effect on transporter affinity. Western blot analysis revealed that LXR activation significantly decreased protein expression of SGLT2 with no change in mRNA level. In addition, LXR activation inhibited canagliflozin-sensitive short-circuit current, which represents SGLT2-mediated glucose transport in a polarized human renal proximal tubular cell monolayer. Furthermore, LXR activation inhibited the transport function of SGLT2 in hyperglycaemic conditions. As such, this study represents evidence for the inhibitory effect of LXR activation on glucose transport in human renal proximal tubular cells.