Otis, J.P., Zeituni, E.M., Thierer, J.H., Anderson, J.L., Brown, A.C., Boehm, E.D., Cerchione, D.M., Ceasrine, A.M., Avraham-Davidi, I., Tempelhof, H., Yaniv, K., Farber, S.A. (2015) Zebrafish as a model for apolipoprotein biology: Comprehensive expression analysis and a role for ApoA-IV in regulating food intake. Disease models & mechanisms. 8(3):295-309.
Improved understanding of lipoproteins, particles that transport lipids throughout the circulation, is vital to developing new treatments for the dyslipidemias associated with metabolic syndrome. A key component of lipoproteins are apolipoproteins, proteins that structure these particles and regulate lipid metabolism through control of cellular lipid exchange. Constraints of cell culture and mouse models importune for a complementary model that can replicate the complex in vivo milieu that regulates apolipoprotein and lipoprotein biology. Here, we further establish the utility of the genetically tractable and optically clear larval zebrafish as a model of apolipoprotein biology. Gene ancestry analyses were implemented to validate the gene names for the zebrafish apolipoprotein A-I (apoA-I), apoB, apoE, and apoA-IV genes and their expression patterns through development were described by whole-mount mRNA in situ hybridization (ISH). The ISH results emphasized the importance of apolipoproteins in transporting yolk and dietary lipids, with universal mRNA expression in the yolk syncytial layer, and intestinal and liver expression observed from 4-6 days post-fertilization (dpf). Furthermore, real-time PCR confirmed that transcription of three of the four zebrafish apoA-IV genes are increased 4 hours after the onset of a 1-hour, high-fat feed. Therefore, we tested the hypothesis that zebrafish ApoA-IV performs a conserved role in the regulation of food intake by transiently overexpressing ApoA-IVb.1 in transgenic larvae and quantifying ingestion of a co-fed fluorescently labeled fatty acid during a high-fat meal as an indicator of food intake. Indeed, ApoA-IVb.1 overexpression decreased food intake by approximately one-third. This study comprehensively describes the expression and function of eleven zebrafish apolipoproteins and serves as a springboard for future investigations to elucidate their roles in development and disease in the larval zebrafish model.