High cholesterol diet modulates macrophage polarization and liver inflammation during early hepatocellular carcinoma progression in zebrafish

Sofia de Oliveira, Ruth A. Houseright, Alyssa L. Graves, Netta Golenberg, Benjamin G. Korte, Veronika Miskolci, Anna Huttenlocher

Research output: Contribution to journalArticlepeer-review

Abstract

Diabetes and obesity have been associated with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and increased incidence of hepatocellular carcinoma (HCC). Here we use optically transparent zebrafish to visualize liver inflammation and disease progression in a NAFLD/NASH-HCC model. We combined a high-cholesterol diet (HCD) with a transgenic zebrafish HCC model induced by hepatocyte-specific activated β-catenin and found that diet induced an increase in liver size and enhanced angiogenesis and neutrophil infiltration in the liver. Although macrophage number was not affected by diet, HCD induced changes in macrophage morphology and polarization with an increase in liver associated TNFα-positive macrophages. Treatment with metformin altered macrophage polarization and reduced liver size in NAFLD/NASH-associated HCC larvae. Moreover, ablation of macrophages limited progression in NAFLD/NASH-associated HCC larvae but not in HCC alone. These findings suggest that HCD alters macrophage polarization and exacerbates the liver inflammatory microenvironment and cancer progression in a zebrafish model of NAFLD/NASH-associated HCC.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Apr 21 2018

Keywords

  • High-cholesterol diet
  • macrophages
  • NAFLD-associated HCC
  • NAFLD/NASH
  • zebrafish model

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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