PUBLICATION

Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish

Authors
de Oliveira, S., Houseright, R.A., Graves, A.L., Golenberg, N., Korte, B.G., Miskolci, V., Huttenlocher, A.
ID
ZDB-PUB-181221-13
Date
2018
Source
Journal of hepatology   70(4): 710-721 (Journal)
Registered Authors
de Oliveira, Sofia, Huttenlocher, Anna
Keywords
High-fat diet, Metformin, NAFLD-associated HCC, NAFLD/NASH, Zebrafish model
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Carcinoma, Hepatocellular/complications*
  • Carcinoma, Hepatocellular/drug therapy*
  • Cell Polarity/drug effects
  • Diet, High-Fat/adverse effects
  • Disease Models, Animal
  • Disease Progression*
  • Hepatocytes/drug effects
  • Hepatocytes/pathology
  • Immunity, Innate/drug effects*
  • Inflammation/drug therapy
  • Inflammation/etiology
  • Liver Neoplasms/complications*
  • Liver Neoplasms/drug therapy*
  • Lymphocytes, Tumor-Infiltrating/drug effects
  • Macrophages/drug effects
  • Macrophages/pathology
  • Metformin/pharmacology
  • Metformin/therapeutic use*
  • Non-alcoholic Fatty Liver Disease/complications*
  • Non-alcoholic Fatty Liver Disease/drug therapy*
  • T-Lymphocytes/drug effects
  • T-Lymphocytes/metabolism
  • Zebrafish
PubMed
30572006 Full text @ J. Hepatol.
Citation
de Oliveira, S., Houseright, R.A., Graves, A.L., Golenberg, N., Korte, B.G., Miskolci, V., Huttenlocher, A. (2018) Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. Journal of hepatology. 70(4):710-721.
Abstract
Background and aims Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is an increasing clinical problem associated with progression to hepatocellular carcinoma (HCC). The effect of high fat diet on the early immune response in HCC is poorly understood. In addition, the role of metformin in treating NAFLD and HCC remains controversial. Here we visualized the early immune responses to the liver and the effect of metformin on progression of HCC using optically transparent zebrafish.
Methods We used live imaging to visualize liver inflammation and disease progression in a NAFLD/NASH-HCC zebrafish model. We combined a high fat diet (HFD) with a transgenic zebrafish HCC model induced by hepatocyte-specific activated beta-catenin and assessed liver size, angiogenesis, micronuclei formation and inflammation in the liver. In addition, we probed the effects of metformin on immune cell composition and early HCC progression.
Results We found that HFD induced an increase in liver size, enhanced angiogenesis, micronuclei formation and neutrophil infiltration in the liver. Although macrophage number was not affected by diet, high fat diet induced changes in macrophage morphology and polarization with an increase in liver associated TNFα positive-macrophages. Treatment with metformin altered macrophage polarization, reduced liver size and micronuclei formation in NAFLD/NASH-associated HCC larvae. Moreover, high fat diet reduced T cell density in the liver and this effect was rescued by treatment with metformin.
Conclusions These findings suggest that diet alters macrophage polarization and exacerbates the liver inflammatory microenvironment and cancer progression in a zebrafish model of NAFLD/NASH-associated HCC. Metformin specifically affects the progression induced by diet and modulates the immune response by affecting macrophage polarization and T cell infiltration, suggesting possible effects of metformin on tumor surveillance.
Lay summary This paper reports a new zebrafish model to study the effects of diet on liver cancer. We found that high-fat diet promotes nonresolving inflammation in the liver and enhances cancer progression. In addition, we found that metformin, a drug used to treat diabetes, inhibits high fat diet-induced cancer progression in this model, by reducing diet-induced nonresolving inflammation and potentially restoring tumor surveillance.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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