Erin Ciske

Metabolic-Dysfunction Associated Steatohepatitis (MASH) is a manifestation of a disease spectrum known as “Metabolic-Dysfunction Associated Steatotic Liver Disease” (MASLD). MASLD affects 32% of the US population and MASH is projected to be the leading cause of liver transplants in the United States in the coming years. MASH is characterized by immune cell-mediated inflammation, accumulation of triglycerides, and fibrosis. Notably, MASH can progress further to hepatocellular carcinoma if left untreated. It has been previously shown that the cytokines and antibodies produced by B cells play an inflammatory role in disease progression. However, little was understood about the metabolic pathways that regulate B cell response. We sought to discover the energetic mechanism that supports the increased activation of hepatic B cells during MASH. We induced MASH in a mouse model and conducted seahorse and ELISA assays. We found that MASH B cells have increased mitochondrial mass and ATP production, both of which were predominantly driven by oxidative phosphorylation (OXPHOS). Next, we investigated the possible substrates that fuel the increased OXPHOS in MASH B cells. We hypothesized that MASH B cells use fatty acids to fuel OXPHOS, however, we found that MASH B cells conducted minimal fatty acid oxidation. Instead, when we inhibited the entry of pyruvate into the mitochondria, MASH B cells were unable to achieve maximal respiration. Furthermore, the production of the inflammatory cytokines TNFa and IL-6 decreased drastically in B cells upon pyruvate oxidation inhibition. Based on these findings, we developed a mouse model where the mitochondrial pyruvate carrier (MPC) was selectively excised in B cells to investigate if pyruvate is required by B cells to promote inflammation and aggravate disease. Overall, these findings advance our understanding of the energetic mechanisms by which B cell-derived inflammation promotes MASH.