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A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

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 h...

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Autores principales: Kulkarni, Abhishek, Ibrahim, Sara, Haider, Isra, Basha, Amina, Montgomery, Emma, Ermis, Ebru, Mirmira, Raghavendra G., Anderson, Ryan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8962409/
https://www.ncbi.nlm.nih.gov/pubmed/35203687
http://dx.doi.org/10.3390/biomedicines10020479
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author Kulkarni, Abhishek
Ibrahim, Sara
Haider, Isra
Basha, Amina
Montgomery, Emma
Ermis, Ebru
Mirmira, Raghavendra G.
Anderson, Ryan M.
author_facet Kulkarni, Abhishek
Ibrahim, Sara
Haider, Isra
Basha, Amina
Montgomery, Emma
Ermis, Ebru
Mirmira, Raghavendra G.
Anderson, Ryan M.
author_sort Kulkarni, Abhishek
collection PubMed
description 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.
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spelling pubmed-89624092022-03-30 A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease Kulkarni, Abhishek Ibrahim, Sara Haider, Isra Basha, Amina Montgomery, Emma Ermis, Ebru Mirmira, Raghavendra G. Anderson, Ryan M. Biomedicines Article 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. MDPI 2022-02-17 /pmc/articles/PMC8962409/ /pubmed/35203687 http://dx.doi.org/10.3390/biomedicines10020479 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kulkarni, Abhishek
Ibrahim, Sara
Haider, Isra
Basha, Amina
Montgomery, Emma
Ermis, Ebru
Mirmira, Raghavendra G.
Anderson, Ryan M.
A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease
title A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease
title_full A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease
title_fullStr A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease
title_full_unstemmed A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease
title_short A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease
title_sort novel 2-hit zebrafish model to study early pathogenesis of non-alcoholic fatty liver disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8962409/
https://www.ncbi.nlm.nih.gov/pubmed/35203687
http://dx.doi.org/10.3390/biomedicines10020479
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