Chonlaket Pattira, Wongwan Teerasak, Soodvilai Sunhapas
Toxicology Graduate Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
Research Center of Transporter Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
Exp Physiol. 2018 Feb 1;103(2):250-260. doi: 10.1113/EP086478. Epub 2017 Dec 20.
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.
本研究的核心问题是什么？据报道，肝脏X受体（LXR）可调节多种膜转运蛋白。研究LXR激活是否调节人肾近端小管细胞中SGLT2介导的葡萄糖转运至关重要。主要发现及其重要性是什么？肝脏X受体激活通过降低SGLT2蛋白表达，在正常和高糖条件下抑制SGLT2转运功能。肝脏X受体（LXRs）是核受体家族的成员，由两种亚型LXRα和LXRβ组成。它们在能量代谢中起主要作用，包括脂质和葡萄糖代谢。最近的研究报道LXRs调节血糖，但其机制仍不确定。本研究调查了LXR激活是否调节人肾近端小管细胞中的钠葡萄糖协同转运蛋白2（SGLT2）。LXR激动剂T0901317和GW3965以浓度依赖性方式抑制SGLT2介导的葡萄糖摄取。LXR拮抗剂非诺贝特减弱了T0901317和GW3965的作用。视黄酸X受体（RXR）激动剂贝沙罗汀的激活增强了这些配体的抑制作用。因此，LXR激动剂对SGLT2的抑制作用分别由LXR和RXR激活介导和促进。此外，LXR激动剂的抑制作用不是由细胞毒性介导的。将肾近端小管细胞系HK-2细胞暴露于LXR激动剂中，显著降低了SGLT2的最大转运速率，而对转运体亲和力没有任何影响。蛋白质印迹分析显示，LXR激活显著降低了SGLT2的蛋白表达，而mRNA水平没有变化。此外，LXR激活抑制了卡格列净敏感的短路电流，这代表了极化的人肾近端小管细胞单层中SGLT2介导的葡萄糖转运。此外，LXR激活在高血糖条件下抑制SGLT2的转运功能。因此，本研究为LXR激活对人肾近端小管细胞葡萄糖转运的抑制作用提供了证据。
