Model Organisms in Drug Discovery

204 LIPID METABOLISM AND SIGNALING IN ZEBRAFISH
and other disorders such as cancer and autoimmune diseases (Calder, 2001;
Gupta and Dubois, 2001; Tilley et al., 2001; Vivanco and Sawyers, 2002).
Although classical studies have defined how lipids are absorbed, transported,
deposited and mobilized, our knowledge of the genetic regulation of these and
other aspects of ‘lipomics’ is far from complete. For these reasons, the analysis
of lipid metabolism remains an active area of biomedical research.
In this chapter, we describe our experience with the zebrafish as a model
system to study mammalian lipid metabolism and signaling. We have shown
that zebrafish process dietary phospholipid and cholesterol in a manner
analogous to humans and other mammals (Farber et al., 2001). We also have
shown that zebrafish and mammals utilize a conserved pathway to regulate the
synthesis of prostanoids, an important class of lipid signaling molecules that
are generated by the action of cyclooxygenases (Grosser et al., 2002). These
similarities of teleost and mammalian physiology are noteworthy because
pharmacological inhibitors of cholesterol synthesis and cyclooxygenases are
among the most commonly prescribed drugs used for the treatment and
prevention of human diseases (Knopp, 1999; Crofford, 2001; Hennekens,
2001; Chau and Cunningham, 2002). Together, these studies confirm the
utility of the zebrafish as a model system for drug discovery in areas related to
the absorption and processing of lipids and their cellular metabolites. Such
studies may have an impact on the development of new strategies for the
treatment and prevention of common human diseases.
8.2 Fish as a model organism to study human
physiology and disease
Through the pioneering work of Streisinger et al. (1981) the zebrafish, Danio
rerio, has developed as an important model system to study vertebrate
development (Haffter et al., 1996). As outlined by Schulte-Merker in
Chapter 7, advantages of the zebrafish include its short generation time,
external fertilization, optically clear embryos and the large number of
offspring produced from a single female. Although advantageous for
embryological studies, these features also have facilitated the performance
of large-scale forward genetic studies using chemical mutagenesis, gamma
irradiation and, most recently, retroviral insertions (Driever et al., 1996;
Haffter et al., 1996; Fisher et al., 1997; Chen et al., 2002). Such studies have
led to the identification of diverse mutant phenotypes that affect embryogenesis
at various developmental stages, including axis formation, gastrulation
and organogenesis. These studies have led to the recognition that genetic
analyses in zebrafish are relevant to biomedical research, given that most
mutants are predicted to derive from single gene defects and that most of these