A diet-independent zebrafish model for NAFLD recapitulates patient lipid profiles and offers a system for small molecule screening

Non-alcoholic Fatty Liver Disease (NAFLD) or pathological hepatic lipid overload, is considered to affect obese individuals. However, NAFLD in lean individuals is prevalent, especially in South Asian population. The path-ophysiology of lean NAFLD is not well understood and most animal models of NAFLD use the high-fat diet paradigm. To bridge this gap, we have developed a diet-independent model of NAFLD in zebrafish. We have previously shown that chronic systemic inflammation causes metabolic changes in the liver leading to hepatic fat accumulation in an IL6 overexpressing (IL6-OE) zebrafish model. In the present study, we compared the hepatic lipid composition of adult IL6-OE zebrafish to the controls and found an accumulation of saturated tri-acylglycerols and a reduction in the unsaturated triacylglycerol species reminiscent of NAFLD patients. Zebrafish is an ideal system for chemical genetic screens. We tested whether the hepatic lipid accumulation in the IL6-OE is responsive to chemical treatment. We found that PPAR-gamma agonist Rosiglitazone, known to reduce lipid overload in the high-fat diet models of NAFLD, could ameliorate the fatty liver phenotype of the IL6-OE fish. Rosiglitazone treatment reduced the accumulation of saturated lipids and showed a concomitant increase in unsaturated TAG species in our inflammation-induced NAFLD model. Our observations suggest that the IL6-OE model can be effective for small molecule screening to identify compounds that can reverse hepatic lipid accumulation, especially relevant to lean NAFLD.

Automated summary

Non-alcoholic Fatty Liver Disease (NAFLD) is not only prevalent in obese individuals, but also in lean individuals, especially in South Asian population. In this study, researchers developed a diet-independent model of NAFLD in zebrafish and found that IL6 overexpression in the zebrafish could lead to hepatic fat accumulation, similar to NAFLD patients. They also discovered that treating the IL6-overexpressing zebrafish with the PPAR-gamma agonist Rosiglitazone could ameliorate the fatty liver phenotype. This research highlights the potential of the IL6-OE zebrafish model for small molecule screening to identify compounds that can reverse hepatic lipid accumulation in lean NAFLD.