A diet-independent zebrafish model for NAFLD recapitulates patient lipid profiles and offers a system for small molecule screening |
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| Affiliation: | 1. Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Palle Juel-Jensens Boulevard 99, 8200 Aarhus, Denmark;2. School of Pharmacy, Liverpool John Moore University, Byrom Street, Liverpool L3 3AF, United Kingdom;1. Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy;2. Department of Translational and Precision Medicine, Sapienza, University of Rome, Rome, Italy;3. Maria Cecilia Hospital, Cotignola, RA, Italy;1. Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan;2. Institute for Advanced Academic Research, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan;1. Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9700RB, the Netherlands;2. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9700RB, the Netherlands;3. Faculty Campus Fryslân, University of Groningen, Leeuwarden, the Netherlands;4. Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France;5. European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;1. Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA;2. Institute of Biosciences & Technology, Texas A&M University, Houston, TX, 77030, USA |
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| Abstract: | 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 pathophysiology 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 triacylglycerols 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. |
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