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 pathways and complementary model systems of hepatic fibrosis. A rare, monogenic disorder in which children with mutations in mannose phosphate isomerase (MPI) develop liver fibr...

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Published inHepatology (Baltimore, Md.) Vol. 70; no. 6; pp. 2107 - 2122
Main Authors DeRossi, Charles, Bambino, Kathryn, Morrison, Joshua, Sakarin, Isabel, Villacorta‐Martin, Carlos, Zhang, Changwen, Ellis, Jillian L., Fiel, M. Isabel, Ybanez, Maria, Lee, Youngmin A., Huang, Kuan‐lin, Yin, Chunyue, Sakaguchi, Takuya F., Friedman, Scott L., Villanueva, Augusto, Chu, Jaime
Format Journal Article
LanguageEnglish
Published United States Wiley Subscription Services, Inc 01.12.2019
Subjects
Animals
Cell activation
Cell culture
Cells, Cultured
Danio rerio
Ethanol
Fatty liver
Fibrosis
Gene expression
Glycosylation
Hepatic Stellate Cells - physiology
Hepatitis B
Hepatology
Humans
Liver Cirrhosis - etiology
Liver diseases
Male
Mannose
Mannose - pharmacology
Mannose-6-Phosphate Isomerase - physiology
Metabolism
Mpi gene
Platelet-Derived Growth Factor - physiology
Signal Transduction - physiology
Supplements
Zebrafish
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Summary:The growing burden of liver fibrosis and lack of effective antifibrotic therapies highlight the need for identification of 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 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 down‐regulated proportionate to fibrosis in chronic liver diseases, including nonalcoholic 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 indicate the prospect that modulation of mannose metabolism pathways could reduce HSC activation and improve hepatic fibrosis.
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.30677