Model Organisms in Drug Discovery

206 LIPID METABOLISM AND SIGNALING IN ZEBRAFISH
Concomitantly, we identified the zebrafish orthologs of the mammalian
cyclooxygenases-1 and -2 genes and showed that they are metabolically active,
and have related pharmacological specificities and physiological roles to those
of their mammalian counterparts. In the following sections we describe these
studies in detail and address the design of screens for genes that contribute to
the regulation of these essential aspects of human physiology.
8.3 Lipid metabolism screen
Many genes known to play important roles in mammalian lipid metabolism
are conserved in the optically clear zebrafish larvae. We have initiated a largescale
N-ethyl-N-nitrosourea (ENU) screening using fluorescent lipid analogs
to identify mutations with perturbed lipid metabolism. In this section, lipid
metabolism in fish, optical biosensors and drug screening are discussed.
Lipid metabolism in fish
Numerous researchers have studied the major components of lipid metabolism
in teleost fish: absorption, transport, storage and mobilization. It is now
clear that lipid transport and mobilization in fish are similar to those observed
in mammals but absorption and storage in fish are slightly different (Sheridan,
1988). In fish, both non-esterified fatty acids and triacylglycerol-enriched
chylomicrons are transported to the liver via the blood circulation. The
lipolysis processes in fish are accomplished by various lipases and hormones
that are similar to those of mammals (Sheridan, 1988, 1994). In addition, the
plasma lipoproteins, including apolipoprotein A- and B-like proteins, are
comparable to mammals (Babin and Vernier, 1989). In mammals, absorption
is accomplished by hydrolyzing lipids such as fatty acids and monoacylglycerol,
re-esterifying them into triacylglycerol and then lipoprotein
loading in enterocytes. These newly made chylomicrons are subsequently
secreted into the lymphatic system for transport to the liver (Tso and
Fujimoto, 1991). Fish, however, not only contain this slow triacylglycerol
delivery system (Sire et al., 1981) but also absorb and deliver fatty acids
directly into the peripheral tissues via the blood circulation (Sheridan et al.,
1985). Mammals deposit lipids primarily in adipose tissue; in contrast, fish
store lipids not only in mesenteric adipose tissue but also in muscle and liver
(Sheridan, 1994). The major stored lipids in fish are triacylglycerol and
polyunsaturated fatty acids, with some minor lipid classes such as
glycerylether analogs and alkoxydiacylglycerol (Sheridan, 1994).
Data from our laboratories have shown that when zebrafish larvae begin
feeding at 5 days post-fertilization, they process dietary lipids in a similar
manner to mammals. This includes lipid hydrolysis in the intestine, lipid