Page 378 - The Toxicology of Fishes

358 The Toxicology of Fishes

recent studies suggest that peroxisome proliferation and AOX expression (typical PPARα-induced liver
responses) may be used as biomarkers in aquatic organisms (Cajaraville et al., 2003). Interestingly,
however, as with gene regulation of CYP2, little evidence suggests that PPARα activation results in
altered expression of CYP4, a common PPARα target in mammals. This again represents a significant
departure in CYP gene regulation between teleosts and mammals. Although CYP4 has been identified
in several fish species (either by direct cloning or by genome analysis), the mechanisms of CYP gene
regulation in teleosts have not been well investigated. Initial similarities between AhR and CYP1A
activation suggested that disparate species would share common mechanisms; however, recent observa-
tions reveal a lack of induction of CYP4 and CYP2 genes in addition to the lack of CAR. CYP gene
regulation in teleosts may be quite different from that of their mammalian counterparts. Moreover, given
the dynamic diversity of teleosts and their diverse habitats, significant differences may be observed in
the spectrum of NR ligands, binding affinities, and mechanisms regulating gene transactivation.

Role of Nuclear Receptors in Bile Acid, Lipid, and Cholesterol Homeostasis
Multiple NRs play pivotal roles in the regulation of cholesterol, lipids, and bile acid in the livers of
mammals. In keeping with the theme that NRs serve as cellular sensors for nutrients and their metabolites,
it is now understood that the effects of many dietary compounds, including cholesterol, fatty acids, and
fat-soluble vitamins, and other lipids, are mediated by the action of NR binding. Nutritional lipid intake
constitutes an important determinant of disease susceptibility and is often exacerbated by dislipidemia.
Numerous studies are now addressing questions of the influence of dietary lipids on gene regulation and
subsequent changes in metabolism with a goal of establishing how diets can be modified to improve
health. Identifying and understanding the activity of nuclear receptors as cellular sensors of cholesterol,
lipids, and bile acids and thus their regulation are the subjects of intense study. Cholesterol is essential
for all vertebrate cells and is required for maintenance of membrane fluidity and permeability, as a
precursor for steroid biosynthesis, and for bile acid production. Homeostatic control of lipoprotein
cholesterol uptake and synthesis is regulated at multiple checkpoints through a series of negative feedback
loops that respond to elevated intracellular cholesterol levels. These checkpoints are governed by a family
of membrane-bound transcription factors—sterol regulatory element binding proteins (SREBPs)—which
activate expression of genes involved in the synthesis and uptake of cholesterol and lipogenesis (Horton
et al., 2002). To prevent cytoxicity due to cholesterol, oxysterol, and bile acid accumulation, liver X
receptor (LXR), farnesol X receptor (FXR), and additional NRs (PXR, LHR, PPAR, HNF4, and SHP)
promote sterol storage, transport, and catabolism (Ory, 2004). Key to the coordinated function of these
receptors is their role as cellular sensors for lipids, sterols, and bile acids (i.e., PPAR, fatty acids; LXR,
oxysterols; FXR, bile acids; PXR/CAR, bile acids). Receptor ligand binding of NRs initiates specific
transcriptional programs that regulate sterol homeostasis, including cholesterol uptake and catabolism,
triglyceride metabolism, reverse cholesterol transport, lipoprotein biosynthesis, and bile acid synthesis,
transport, and metabolism (Chiang, 2004; Ory, 2004).
Completion of genome projects in certain teleosts such as pufferfish, medaka, and zebrafish demon-
strated the presence of LXR, FXR, and other NRs associated with cholesterol and lipid homeostasis.
These results suggested a similar repertoire of NR function in lower vertebrates. To date, however,
information regarding the functional mechanism of NRs in sterol homeostasis in teleosts and other
aquatic organisms is lacking and can only be inferred via gene homologies. Identification of many of
the genes regulated by these NRs including CYPs, apolipoproteins, and various transporters, however,
has provided the additional information that teleosts share a common mechanism of sterol homeostasis
with mammalian liver.

Summary
Nuclear receptors are ligand-dependent transcription factors that bind to lipophilic signaling molecules,
resulting in the control and expression of target genes in liver and often other tissues. They facilitate the
cellular response to endogenous and exogenous ligands by coordinating complex transcriptional
responses; therefore, they must be considered in the study of toxicity. Analysis of the evolution, molecular