SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8⁺ T cell activation

Area of Science:

• Immunology
• Metabolic Diseases
• Pharmacology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) involves CD8+ T cell accumulation, driving liver injury.
• Empagliflozin (EMPA), an SGLT2 inhibitor, shows promise for MASH, but its mechanism is unclear.

Purpose of the Study:

• To elucidate the mechanism by which empagliflozin ameliorates MASH.
• To investigate the role of CD8+ T cells in EMPA's therapeutic effects.

Main Methods:

• Mice models of MASH treated with EMPA.
• Analysis of hepatic CD8+ T cell accumulation and granzyme B levels.
• Investigation of beta-hydroxybutyric acid, 3-hydroxybutyrate dehydrogenase 1 (Bdh1), and interferon regulatory factor 4 (Irf4) in CD8+ T cells.
• T cell-specific Bdh1 knockout mouse model.
• Case-control study in MASH patients treated with SGLT2 inhibitors.

Main Results:

• EMPA reduced hepatic CD8+ T cell accumulation and granzyme B levels in MASH mice.
• EMPA increased beta-hydroxybutyric acid in CD8+ T cells by upregulating Bdh1, inhibiting Irf4.
• Bdh1 ablation in T cells worsened MASH and EMPA efficacy.
• SGLT2 inhibitor treatment reduced CD8+ T cell infiltration and liver injury in MASH patients.

Conclusions:

• SGLT2 inhibitors target CD8+ T cells in MASH through a mechanism involving beta-hydroxybutyric acid production.
• Empagliflozin's therapeutic effect in MASH is partly mediated by inhibiting CD8+ T cell activation.
• SGLT2 inhibitors represent a potential therapeutic strategy for MASH by modulating T cell responses.