Abstract

Background: Sphingosine-1 phosphate (S1P) is a bioactive lipid molecule that modulates inflammation and hepatic lipid metabolism in MASLD, which affects 1 in 3 people and increases the risk of liver fibrosis and hepatic cancer. S1P can be generated by 2 isoforms of sphingosine kinase (SphK). SphK1 is well-studied in metabolic diseases. In contrast, SphK2 function is not well characterized. Both sphingolipid and redox metabolism dysregulation contribute to MASLD pathologic progression. While SphK2 localizes to both the nucleus and mitochondria, its specific role in early MASH is not well defined. Methods: This study examined SphK2 depletion effects on hepatic redox metabolism, mitochondrial function, and inflammation in a 16-week western diet plus sugar water (WDSW)-induced mouse model of early MASH. Results: WDSW- SphK2 −/− mice exhibit increased hepatic lipid accumulation and hepatic redox dysregulation. In addition, mitochondria-localized cholesterol and S1P precursors were increased. We traced SphK2 −/− -mediated mitochondrial electron transport chain impairment to respiratory complex-IV and found that decreased mitochondrial redox metabolism coincided with increased oxidase gene expression and oxylipin production. Consistent with this relationship, we observed pronounced increases in hepatic inflammatory gene expression, prostaglandin accumulation, and innate immune homing in WDSW- SphK2 −/− mice compared to WDSW-wild-type mice. Conclusions: These studies suggest SphK2-derived S1P maintains hepatic redox metabolism and describe the potential consequences of SphK2 depletion on proinflammatory gene expression, lipid mediator production, and immune infiltration in MASH progression.