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09

2024

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09

Engelie net new use! The latest research from Southern Medical University shows that SGLT2 inhibitors promote ketogenic and improve MASH by inhibiting CD8 T cell activation.

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Accumulation of autoaggressive CD8 T cells contributes significantly to liver injury and inflammation during the progression of metabolic dysfunction-associated steatohepatitis (MASH).EMPA, a highly selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has potential therapeutic effects on hepatic steatosis; however, the underlying mechanism has not been fully elucidated.

On September 6, 2024, Zhang Huijie, Yang Wei and Li Jin of Southern Medical University jointly communicatedCell Metabolism（IF=27.7）Published online entitled“SGLT2 inhibitor promote ketogenesis to improve MASH by suppressing CD8+T cell activation”The research paper,The study showedSGLT2 inhibitors inhibit CD8+T cell activation promotes ketogenesis and improves MASH.

Here, the researchers found that EMPA significantly reduced the autoinvasive CD8+Liver accumulation of T cells reduced granzyme B levels in MASH mice. Mechanically, EMPA increases 3-hydroxybutyrate dehydrogenase 1 (Bdh1), promote the expression of CD8+T-cell ketogenesis, which increases beta-hydroxybutyrate. β-hydroxybutyric acid subsequently inhibits interferon regulatory factor 4 (Irf4), this is CD8+Key to T cell activation. In addition, in T cellsBdh1Ablation of MASH aggravates the performance of MASH and hinders the therapeutic effect of EMPA. In addition, a case-control study also showed that SGLT2 inhibitor treatment inhibited CD8+T cell infiltration, improved liver injury in MASH patients.Taken together, the study suggests that SGLT2 inhibitors can target CD8+T cells, may be an effective strategy for the treatment of MASH.

Metabolic dysfunction-associated steatosis liver disease (MASLD) is a global health problem with increasing prevalence worldwide. Metabolic dysfunction-associated steatohepatitis (MASH) is a more severe stage of MASLD, characterized by excessive fat accumulation, inflammation, hepatocellular damage, and fibrosis. This is of particular concern because it may progress to cirrhosis, liver failure or hepatocellular carcinoma. Although there are many studies exploring drug therapy, there is currently no consensus on the optimal treatment for MASH.

Dysregulation of innate and adaptive immunity in the liver, followed by inflammation, has a key role in the development of MASH. In T-lymphocyte subsets, CD8+T cells and CD4+T cells are important contributors to adaptive immunity.CD8 T cells, especially cytotoxic T lymphocytes (CTLs), exert their effector function by releasing cytokines such as granzyme B (GZMB) and interferon gamma (IFN-γ), while CD4+T cells play a regulatory role in maintaining the function of other immune cell populations.Previous studies have shown that CD8+T cells, as pro-inflammatory cells, regulate the progression of MASH. In addition, CD8+T cells preferentially utilize non-glucose physiologic carbon sources as metabolic fuel, and their activation and effector functions are modulated by carbon availability Several studies have highlighted the potential of modulating ketone body metabolism as a promising means of modulating T cell activation and effects.

Ketone bodies enhance the support CD8 in response to bacterial infection and tumor +T-cell function of respiratory capacity and tricarboxylic acid (TCA) cycle-dependent metabolic pathways. β-OHB is CD8+T cells produce a key substrate for acetyl-CoA (CoA) and influence their effector responses by affecting histone acetylation. However, during MASH progression, CD8+The specific changes in ketone body metabolism and subsequent functional alterations in T cells remain unknown.In addition, sodium-glucose cotransporter 2 inhibitors (SGLT2i) increase ketone body levels and have a protective effect on the kidney and cardiovascular system by promoting ketogenesis. Several clinical studies have also suggested that SGLT2i may ameliorate hepatic steatosis and liver enzyme levels in MASLD, suggesting their potential beneficial effects on MASH progression.
In this study, the authors observed that SGLT2i regulates CD8 +The ketogenic action of T cells effectively slows the progression of MASH, thereby inhibiting their activation and effector functions in MASH mouse models and MASH patients. This highlights the targeting of ketogenic and CD8 +Potential therapeutic value of T-cell response therapy for MASH. The study provides evidence that SGLT2i promotes ketone body synthesis, resulting in CD8+T-cell infiltration and effector functions are reduced, thereby improving MASH progression.The hepatoprotective effect observed by modulating ketone body metabolism is mediated by inhibition Irf4expression and activity are mediated. Results obtained from animal and human MASH models suggest that targeting CD8+T cell activation and ketone body metabolism may be a potential approach for the treatment of MASH.

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