SGLT2 inhibitors ameliorate NAFLD in mice via downregulating PFKFB3, suppressing glycolysis and modulating macrophage polarization

• Published in: Acta pharmacologica Sinica 2024-12, Vol.45 (12), p.2579-2597
• Main Authors: Lin, Xia-fang, Cui, Xiao-na, Yang, Jin, Jiang, Ya-fei, Wei, Tian-jiao, Xia, Li, Liao, Xin-yue, Li, Fei, Wang, Dan-dan, Li, Jian, Wu, Qi, Yin, De-shan, Le, Yun-yi, Yang, Kun, Wei, Rui, Hong, Tian-pei
• Format: Article
• Language: English
• Subjects: Animals; Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Biomedical and Life Sciences; Biomedicine; Canagliflozin - pharmacology; Canagliflozin - therapeutic use; Down-Regulation - drug effects; Glucosides - pharmacology; Glucosides - therapeutic use; Glycolysis - drug effects; Humans; Immunology; Internal Medicine; Macrophages - drug effects; Macrophages - metabolism; Male; Medical Microbiology; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; Pharmacology/Toxicology; Phosphofructokinase-2 - antagonists & inhibitors; Phosphofructokinase-2 - metabolism; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Vaccine
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/s41401-024-01389-3

Sodium-glucose co-transporter 2 (SGLT2) inhibitor (SGLT2i) is a novel class of anti-diabetic drug, which has displayed a promising benefit for non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the protective effects of SGLT2i against NAFLD and the underlying mechanisms. The db/db mice and western diet-induced NAFLD mice were treated with dapagliflozin (1 mg·kg −1 ·d −1 , i.g.) or canagliflozin (10 mg·kg −1 ·d −1 , i.g.) for 8 weeks. We showed that the SGLT2i significantly improved NAFLD-associated metabolic indexes, and attenuated hepatic steatosis and fibrosis. Notably, SGLT2i reduced the levels of pro-inflammatory cytokines and chemokines, downregulated M1 macrophage marker expression and upregulated M2 macrophage marker expression in liver tissues. In cultured mouse bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages, the SGLT2i (10, 20 and 40 μmol/L) significantly promoted macrophage polarization from M1 to M2 phenotype. RNA sequencing, Seahorse analysis and liquid chromatography-tandem mass spectrometry analysis revealed that the SGLT2i suppressed glycolysis and triggered metabolic reprogramming in macrophages. By using genetic manipulation and pharmacological inhibition, we identified that the SGLT2i targeted PFKFB3, a key enzyme of glycolysis, to modulate the macrophage polarization of M1 to M2 phenotype. Using a co-culture of macrophages with hepatocytes, we demonstrated that the SGLT2i inhibited lipogenesis in hepatocytes via crosstalk with macrophages. In conclusion, this study highlights a potential therapeutic application for repurposing SGLT2i and identifying a potential target PFKFB3 for NAFLD treatment.