肝细胞中钠-葡萄糖共转运蛋白 2 的表达增加和 O-GlcNAc 化导致非酒精性脂肪性肝炎。
Increased expression of sodium-glucose cotransporter 2 and O-GlcNAcylation in hepatocytes drives non-alcoholic steatohepatitis.
机构信息
Interdisciplinary Program of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, Republic of Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.; Division of Endocrine and Kidney Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju-si, Chungbuk 28159, Republic of Korea.
出版信息
Metabolism. 2023 Aug;145:155612. doi: 10.1016/j.metabol.2023.155612. Epub 2023 Jun 3.
AIMS
Steatosis reducing effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-alcoholic steatohepatitis (NASH) has been consistently reported in humans, but their mechanism remains uncertain. In this study, we examined the expression of SGLT2 in human livers and investigated the crosstalk between SGLT2 inhibition and hepatic glucose uptake, intracellular O-GlcNAcylation, and autophagic regulation in NASH.
MATERIALS AND METHODS
Human liver samples obtained from subjects with/without NASH were analyzed. For in vitro studies, human normal hepatocytes and hepatoma cells were treated with SGLT2 inhibitor under high-glucose and high-lipid conditions. NASH in vivo was induced by a high-fat, -fructose, and -cholesterol Amylin liver NASH (AMLN) diet for 10 weeks followed by an additional 10 weeks with/without SGLT2 inhibitor (empagliflozin 10 mg/kg/day).
RESULTS
Liver samples from subjects with NASH were associated with increased SGLT2 and O-GlcNAcylation expression compared with controls. Under NASH condition (in vitro condition with high glucose and lipid), intracellular O-GlcNAcylation and inflammatory markers were increased in hepatocytes and SGLT2 expression was upregulated; SGLT2 inhibitor treatment blocked these changes by directly reducing hepatocellular glucose uptake. In addition, decreased intracellular O-GlcNAcylation by SGLT2 inhibitor promoted autophagic flux through AMPK-TFEB activation. In the AMLN diet-induced NASH mice model, SGLT2 inhibitor alleviated lipid accumulation, inflammation, and fibrosis through autophagy activation related to decreased SGLT2 expression and O-GlcNAcylation in the liver.
CONCLUSIONS
This study firstly demonstrates increased SGLT2 expression in NASH and secondly reveals the novel effect of SGLT2 inhibition on NASH through autophagy activation mediated by inhibition of hepatocellular glucose uptake and consequently decreased intracellular O-GlcNAcylation.
目的
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂在非酒精性脂肪性肝炎（NASH）中的脂肪减少作用已在人体中得到一致报道，但作用机制尚不清楚。在这项研究中，我们检测了 SGLT2 在人肝脏中的表达，并研究了 SGLT2 抑制与肝葡萄糖摄取、细胞内 O-GlcNAc 化和自噬调节之间的相互作用在 NASH 中的作用。
材料和方法
分析了来自有/无 NASH 患者的人肝组织样本。对于体外研究，在高糖和高脂条件下用 SGLT2 抑制剂处理人正常肝细胞和肝癌细胞。通过高脂肪、高果糖和高胆固醇 Amylin 肝 NASH（AMLN）饮食诱导 NASH 动物模型 10 周，随后再用/不用 SGLT2 抑制剂（恩格列净 10mg/kg/天）治疗 10 周。
结果
与对照组相比，有 NASH 的患者肝组织中 SGLT2 和 O-GlcNAc 化表达增加。在 NASH 条件下（体外高糖和高脂条件），肝细胞内 O-GlcNAc 化和炎症标志物增加，SGLT2 表达上调；SGLT2 抑制剂治疗通过直接减少肝细胞葡萄糖摄取来阻断这些变化。此外，SGLT2 抑制剂降低细胞内 O-GlcNAc 化通过 AMPK-TFEB 激活促进自噬流。在 AMLN 饮食诱导的 NASH 小鼠模型中，SGLT2 抑制剂通过减少 SGLT2 表达和肝脏中 O-GlcNAc 化，通过激活自噬减轻脂质积累、炎症和纤维化。
结论
本研究首次证明了 SGLT2 在 NASH 中的表达增加，其次揭示了 SGLT2 抑制通过抑制肝细胞葡萄糖摄取，进而降低细胞内 O-GlcNAc 化，激活自噬来治疗 NASH 的新作用。
Zotero 插件