1164-P: A Zebrafish Nonalcoholic Fatty Liver Disease Model Links Liver Inflammation with Pancreatic Inflammation and Hyperglycemia

Abstract

The spectrum of nonalcoholic liver disease (NAFLD) ranges from simple steatosis to steatohepatitis with the latter having the potential to irreversibly progress to cirrhosis. Compared with the general population, NAFLD is more frequently seen in patients with type 2 diabetes (T2D), and conversely, NAFLD is associated with increased incidence of T2D. Existing rodent models of NAFLD focus narrowly on certain stages of liver damage and insufficiently encompass all metabolic changes, limiting their utility. The aims of this study were to develop a new model of NAFLD in young zebrafish and use it to probe the associations between liver inflammation and pancreatic islet function. We examined hepatopancreatic inflammation under three conditions: (1) in a zebrafish line (fabp10-CETI-PIC3) in which liver-specific expression of pro-inflammatory cytokines IL-1β, TNFα, and IFN-γ was induced by doxycycline treatment (M1); (2) in wild-type zebrafish fed a high-fat diet (M2); and (3) in a combination of these models (M3). All three conditions showed increased expression of inflammatory cytokines compared to Tg(fabp10:cre) control larvae, and when compared to controls, all three showed increased macrophage infiltration in the liver. Strikingly, staining with CellRox Deep Red to assess reactive oxygen species (ROS)-mediated stress in the liver revealed a 2-fold increase in the M3 combination model, but not in either M1 or M2. Further, although all models showed hyperglycemia, decreased insulin transcription without β cell death, and ROS accumulation in the pancreas, only the M3 condition demonstrated a significant increase in macrophage infiltration of the pancreatic islets as compared to controls. In sum, our novel zebrafish model of liver steatosis and steatohepatitis is a promising model in which to study the intricate associations between NAFLD and T2D, and may serve as an amenable platform for screening novel pharmaceutical interventions. Disclosure S. Ibrahim: None. I. Haider: None. A. Kulkarni: None. I. Doycheva: None. R. G. Mirmira: Advisory Panel; Self; Hibercell Inc., Sigilon Therapeutics, Inc., Veralox Therapeutics, Employee; Spouse/Partner; Beta Bionics, Inc. E. K. Sims: None. R. Anderson: None.