Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Endocrinology, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Cell Metab. 2024 Oct 1;36(10):2245-2261.e6. doi: 10.1016/j.cmet.2024.08.005. Epub 2024 Sep 6.
During the progression of metabolic dysfunction-associated steatohepatitis (MASH), the accumulation of auto-aggressive CD8 T cells significantly contributes to liver injury and inflammation. Empagliflozin (EMPA), a highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), exhibits potential therapeutic benefits for liver steatosis; however, the underlying mechanism remains incompletely elucidated. Here, we found that EMPA significantly reduced the hepatic accumulation of auto-aggressive CD8 T cells and lowered granzyme B levels in mice with MASH. Mechanistically, EMPA increased β-hydroxybutyric acid by promoting the ketogenesis of CD8 T cells via elevating 3-hydroxybutyrate dehydrogenase 1 (Bdh1) expression. The β-hydroxybutyric acid subsequently inhibited interferon regulatory factor 4 (Irf4), which is crucial for CD8 T cell activation. Furthermore, the ablation of Bdh1 in T cells aggravated the manifestation of MASH and hindered the therapeutic efficacy of EMPA. Moreover, a case-control study also showed that SGLT2 inhibitor treatment repressed CD8 T cell infiltration and improved liver injury in patients with MASH. In summary, our study indicates that SGLT2 inhibitors can target CD8 T cells and may be an effective strategy for treating MASH.
在代谢功能障碍相关脂肪性肝炎（MASH）的进展过程中，自身攻击性 CD8 T 细胞的积累显著导致肝损伤和炎症。恩格列净（EMPA）是一种高度选择性的钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂，对肝脂肪变性具有潜在的治疗益处；然而，其潜在机制仍不完全清楚。在这里，我们发现 EMPA 可显著减少 MASH 小鼠肝脏中自身攻击性 CD8 T 细胞的积累并降低颗粒酶 B 水平。从机制上讲，EMPA 通过提高 3-羟丁酸脱氢酶 1（Bdh1）的表达促进 CD8 T 细胞的酮生成，从而增加 β-羟丁酸。随后，β-羟丁酸抑制了干扰素调节因子 4（Irf4），这对于 CD8 T 细胞的激活至关重要。此外，T 细胞中 Bdh1 的缺失加剧了 MASH 的表现，并阻碍了 EMPA 的治疗效果。此外，一项病例对照研究还表明，SGLT2 抑制剂治疗可抑制 CD8 T 细胞浸润并改善 MASH 患者的肝损伤。总之，我们的研究表明，SGLT2 抑制剂可以靶向 CD8 T 细胞，可能是治疗 MASH 的有效策略。
