Low
oxygen levels (
hypoxia) play a role in clinical conditions such as
stroke, chronic
ischemia, and
cancer. To better understand these diseases, it is crucial to study the responses of vertebrates to
hypoxia. Among vertebrates, some teleosts have developed the ability to adapt to extremely low
oxygen levels. We have studied long-term adaptive responses to
hypoxia in adult zebrafish. We used zebrafish that survived severe hypoxic conditions for 3 wk and showed adaptive behavioral and phenotypic changes. We used
cDNA microarrays to investigate
hypoxia-induced changes in expression of 15,532 genes in the respiratory organs (the gills). We have identified 367 differentially expressed genes of which 117 showed
hypoxia-induced and 250
hypoxia-reduced expressions. Metabolic depression was indicated by repression of genes in the TCA cycle in the electron transport chain and of genes involved in protein biosynthesis. We observed enhanced expression of the monocarboxylate transporter and of the
oxygen transporter
myoglobin. The
hypoxia-induced group further included the genes for Niemann-Pick C disease and for
Wolman disease [
lysosomal acid lipase (LAL)]. Both diseases lead to a similar intra- and extracellular accumulation of
cholesterol and
glycolipids. The Niemann-Pick C
protein binds to
cholesterol from internal lysosomal membranes and is involved in
cholesterol trafficking. LAL is responsible for lysosomal
cholesterol degradation. Our data suggest a novel adaptive mechanism to
hypoxia, the induction of genes for lysosomal
lipid trafficking and degradation. Studying physiological responses to
hypoxia in species tolerant for extremely low
oxygen levels can help identify novel regulatory genes, which may have important clinical implications.