Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans

The growing burden of liver fibrosis and lack of effective antifibrotic therapies highlight the need for identification of novel pathways and complementary model systems of hepatic fibrosis. A rare, monogenic disorder in which children with mutations in mannose phosphate isomerase (MPI) develop liver fibrosis led us to explore the overlooked function of MPI and mannose metabolism in liver development and adult liver diseases. Herein, analyses of transcriptomic data from three human liver cohorts demonstrate that MPI gene expression is downregulated proportionate to fibrosis in chronic liver diseases, including non‐alcoholic fatty liver disease and hepatitis B virus. Depletion of MPI in zebrafish liver in vivo and in human hepatic stellate cell (HSC) lines in culture activates fibrotic responses, indicating that loss of MPI promotes HSC activation. We further demonstrate that mannose supplementation can attenuate HSC activation, leading to reduced fibrogenic activation in zebrafish, culture‐activated HSCs, and in ethanol‐activated HSCs. Conclusion: These data introduce the novel prospect that modulation of mannose metabolism pathways could reduce HSC activation and improve hepatic fibrosis.