PT  - JOURNAL ARTICLE
AU  - Sofia de Oliveira
AU  - Ruth A. Houseright
AU  - Alyssa L. Graves
AU  - Netta Golenberg
AU  - Benjamin G. Korte
AU  - Veronika Miskolci
AU  - Anna Huttenlocher
TI  - High cholesterol diet modulates macrophage polarization and liver inflammation during early hepatocellular carcinoma progression in zebrafish
AID  - 10.1101/299016
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 299016
4099  - http://biorxiv.org/content/early/2018/04/21/299016.short
4100  - http://biorxiv.org/content/early/2018/04/21/299016.full
AB  - 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.Abbreviations used in this paperNAFLDNonalcoholic fatty liver diseaseNASHnonalcoholic steatohepatitisHCChepatocellular carcinomaHCDhigh-cholesterol dietTMEtumor microenvironmentTNFtumor necrosis factordpfdays post-fertilizationNDnormal dietMTZmetronidazoleNTRnitroreductase.Authors ContributionConceived and designed experiments: SDO and AH. Performed experiments: SDO, RAH, AG, NG, BGK and VM. Performed analysis: SDO, RAH, AG and VM. Wrote the manuscript: SDO. Critically reviewed and edited the manuscript: RAH, NG, VM and AH