Pyruvate Oxidation Sustains B Cell Antigen-Specific Activation to Exacerbate MASH

• DOI: 10.1101/2023.11.13.566832
• Publication Date: 2023-11-15T19:50:12Z
• Authors: Fanta Barrow; Haiguang Wang; Gavin Fredrickson; Kira Florczak; Erin Ciske; Shalil Khanal; Preethy Parthiban; Huy Nguyen; Enrique Rios; Enis Kostallari; Xavier S. Revelo
• Keywords: Steatohepatitis; Steatosis; Hepatic stellate cell

ABSTRACT B cells play a crucial role in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH), severe form steatotic liver disease that if persistent can lead to cirrhosis, failure, and cancer. Chronic inflammation fibrosis are key features MASH determine progression outcomes. Recent advances have revealed pathogenic cell-derived cytokines antibodies promote development MASH. However, mechanisms through which adaptations underlying their responses remain unclear. Here, we report subset mature with heightened cytokine accumulate To meet increased energetic demand effector responses, increase ATP production via oxidative phosphorylation (OXPHOS) fueled by pyruvate oxidation cell receptor (BCR)-specific manner. Blocking completely abrogated inflammatory capacity cells. Accordingly, restriction BCR led attenuation, including reductions steatosis, hepatic inflammation, fibrosis. Mechanistically, decreased maturation, activation, liver, accompanied T cell- macrophage-mediated inflammation. Notably, attenuated BCR-restricted mice was associated lower IgG expression Fc-gamma receptors on stellate Together, these findings indicate for antigen-specific promoting during