PUBLICATION

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

Authors
DeRossi, C., Bambino, K., Morrison, J., Sakarin, I., Villacorta-Martin, C., Zhang, C., Ellis, J.L., Fiel, M.I., Ybanez, M., Lee, Y.A., Huang, K.L., Yin, C., Sakaguchi, T.F., Friedman, S.L., Villanueva, A., Chu, J.
ID
ZDB-PUB-190425-15
Date
2019
Source
Hepatology (Baltimore, Md.)   70(6): 2107-2122 (Journal)
Registered Authors
Bambino, Kathryn, Chu, Jaime, DeRossi, Charles, Ellis, Jillian, Sakaguchi, Takuya, Yin, Chunyue
Keywords
antifibrotic, cirrhosis, congenital disorder of glycosylation, fibrogenesis, metabolism
MeSH Terms
  • Animals
  • Cells, Cultured
  • Glycosylation
  • Hepatic Stellate Cells/physiology*
  • Humans
  • Liver Cirrhosis/etiology*
  • Male
  • Mannose/pharmacology*
  • Mannose-6-Phosphate Isomerase/physiology*
  • Platelet-Derived Growth Factor/physiology
  • Signal Transduction/physiology
  • Zebrafish
PubMed
31016744 Full text @ Hepatology
Abstract
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. This article is protected by copyright. All rights reserved.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping