Model Organisms in Drug Discovery

218 LIPID METABOLISM AND SIGNALING IN ZEBRAFISH
mutations from mutagenized sperm offer the promise of generating libraries of
mutant alleles that can be assayed in live fish generated through in vitro
fertilization (Draper et al., 2001; Wienholds et al., 2002). This methodology,
commonly referred to as ‘TILLING’ (McCallum et al., 2000), offers the
chance to perform a comprehensive analysis of genes regulating prostanoid
synthesis and activity.
8.6 Summary
Recent work has shown that it is possible to assay phospholipid metabolism
and prostanoid synthesis in zebrafish (Farber et al., 1991; Grosser et al., 2002).
These preliminary studies suggest that important questions of lipid biology are
amenable to large-scale, high-throughput analyses in this model system. Lipid
metabolism now can be added to the growing list of vertebrate developmental
and physiological processes that can be assayed in zebrafish. The potential to
identify novel genes (or novel functions of known genes) that regulate the
metabolism of dietary lipids or the generation of lipid signaling molecules has
important pharmacological implications. By using this strategy, ultimately it
may be possible to devise combined biochemical and physiological assays of
small-molecule modulators of lipid metabolism. Such studies may provide a
rapid and accurate screening methodology of great pharmacological value. As
an example, a recent pilot screen of 640 bioavailable compounds from a
chemical library (Prestwick Chemicals) identified several compounds that
inhibit the accumulation of gall bladder fluorescence in zebrafish larvae fed
the quenched lipid reporter PED6 (A. Rubinstein, Zygogen, Inc., personal
communication). Multiple developmental and physiological pathways are
predicted to have an impact on PED6 processing. Some of these, such as lipid
absorption and transport, have important clinical implications and their
analysis may prove to be tractable using zebrafish-based assays.
8.7 References
Amatruda, J. F., Shepard, J. L., Stern, H. M. and Zon, L. I. (2002). Zebrafish as a cancer
model system. Cancer Cell 1, 229–231.
Babin, P. J. and Vernier, J. M. (1989). Plasma lipoproteins in fish. J. Lipid Res. 30, 467–
489.
Barut, B. A. and Zon, L. I. (2000). Realizing the potential of zebrafish as a model for
human disease. Physiol. Genom. 2, 49–51.
Calder, P. C. (2001). Polyunsaturated fatty acids, inflammation, and immunity. Lipids 36,
1007–1024.
Chan, J., Bayliss, P. E., Wood, J. M. and Roberts, T. M. (2002). Dissection of angiogenic
signaling in zebrafish using a chemical genetic approach. Cancer Cell 1, 257–267.