Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 24, 2019
- Source ID
- 10.1002/hep.30677
Entities
People
- Augusto Villanueva
- Carlos Villacorta-Martín
- Changwen Zhang
- Charles DeRossi
- Chunyue Yin
- Isabel Sakarin
- Jaime Chu
- Jillian L. Ellis
- Joshua Morrison
- Kathryn Bambino
- Kuan‐lin Huang
- M. Isabel Fiel
- Maria Ybanez
- Scott L. Friedman
- Takuya F. Sakaguchi
- Youngmin A. Lee
Organizations
- Boston University
- Cincinnati Children's Hospital Medical Center
- Cleveland Clinic
- Icahn School of Medicine at Mount Sinai
- The Rockefeller University