Nonalcoholic fatty liver disease (
NAFLD) is one of the most common
liver diseases in adults.
NAFLD progresses from benign liver fat accumulation to liver
inflammation and
cirrhosis, and ultimately leads to
liver failure. Although several rodent models have been established for studying
NAFLD, they have limitations that include cost, speed of disease development, key dissimilarities, and poor amenability to pharmacological screens. Here, we present a novel 2-hit zebrafish model to replicate aspects of
NAFLD pathogenesis. We fed zebrafish larvae a high-fat diet (HFD) to drive liver fat accumulation (first hit). Next, we exacerbated liver-specific
inflammation using a transgenic line (fabp10-CETI-PIC3) that induces the expression of proinflammatory
cytokines following induction with
doxycycline (second hit). These hits promoted fat accumulation and liver
inflammation, as demonstrated by the high expression of inflammatory
cytokines, macrophage infiltration, stress induction, and hepatic lipid droplet accumulation. Furthermore, zebrafish in this paradigm showed deranged
glucose metabolism. To validate a small-molecule screening approach, we treated HFD-fed fish with
pioglitazone, a drug shown to be beneficial for
NAFLD in humans, and measured a sharp reduction in liver
lipid accumulation. These results demonstrate new utility for zebrafish in modeling early
NAFLD pathogenesis and demonstrate their feasibility for in vivo screening of new pharmacological interventions.