Western diet induces MASLD and major transcriptional reprogramming in the liver-gut axis of early zebrafish larvae

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to western diet and sedentary lifestyle. While larval zebrafish are powerful discovery tools, standardized diets inducing early-stage MASLD are lacking. Here, we developed and early-stage zebrafish MASLD model (9–12 days post fertilization), using a custom western diet (WD) enriched in palmitate, cholesterol, and fructose. Time dependent fat accumulation and gut-liver histopathological changes were assessed, alongside affordable bulk RNA sequencing across diets and time points. The WD effectively induced hepatic steatosis and hepatocyte ballooning, alongside lipid accumulation in the intestinal bulb. While boiled egg yolk (BEY) triggers strong lipid accumulation, it also induces hepatic sinusoid lipid accumulation and dilation. High throughput transcriptomic analysis revealed that WD triggers a suppression of cholesterol and lipid biosynthesis while BEY activates cholesterol biosynthesis and cyp7a1 expression compared to the regular diet fed larvae with same regime. WD further activated lipid transport signatures and stress-adaptive ribosome biogenesis by 12 dpf. This study features WD as an effective inducer of early MASLD in early-stage zebrafish larvae at a stage amenable to larval drug screening.