Targeting shingolipids inhibits alcohol-induced liver disease

Abstract

Abstract Chronic alcohol consumption is accompanied by intestinal inflammation. However, little is known about how alterations to the intestinal immune system and sphingolipids contribute to pathogenesis of alcoholic liver disease (ALD). We used WT mice, RORγt-deficient mice and sphingosine kinase-deficient mice in a chronic-binge ethanol feeding model. Targeted lipidomics assessed the sphingolipids in gut and liver samples. Ethanol-fed and control mice were treated by SK1 inhibitor. Gut immune cell populations, the amounts of sphingolipids, and the level of liver injury were examined. We found that alcohol intake induces an increase in Th17 cells in the gut. Increased Th17 cells were due to upregulation of SK1 activity and Rorc activation. The pathogenic role of S1P/S1PR1 signaling in ALD was attributable to the migration and activation of Th17 cells. Importantly, deletion of SK1 markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. In conclusion, our findings suggest that S1P signaling was crucial in the pathogenesis of alcoholic liver disease in a Th17 cell dependent manner.