Gene expression of the liver in response to chronic hypoxia

Abstract

Hypoxia is an important ecological, evolutionary, and biomedical stressor. While physiological acclimatization of mammals to hypoxia is well studied, the variation in gene expression that underlies acclimatization is not well studied. We acclimatized inbred mice for 32 days to hypoxic conditions that simulated altitudes of 1400, 3000, and 4500 m. We used oligonucleotide microarrays to measure changes in steady-state abundance of mRNA in the livers of these mice. Mice exposed to more severe hypoxia (simulated altitude of 4500 m) were smaller in mass and had higher hematocrit than mice exposed to less severe hypoxia. ANOVA and false discovery rate tests indicated that 580 genes were significantly differentially expressed in response to chronic hypoxia. Few of these 580 genes have previously been reported to respond to hypoxia. In contrast, many of these 580 genes belonged to same functional groups typically respond to acute hypoxia. That is, both chronic and acute hypoxia elicit changes in transcript abundance for genes involved in angiogenesis, glycolysis, lipid metabolism, carbohydrate metabolism, and protein amino acid phosphorylation, but the particular genes affected by the two types of hypoxia were mostly different. Numerous genes affecting the immune system were differentially expressed in response to chronic hypoxia, which supports recently proposed hypotheses that link immune function and hypoxia. Furthermore, our results discovered novel elevated mRNA abundance of genes involved in hematopoiesis and oxygen transport not reported previously, but consistent with extreme hematocrits found in hypoxic mice.

Differential effects of chronic hypoxia and feed restriction on the expression of leptin and its receptor, food intake regulation and the endocrine stress response in common carp

“…These results concur with mammalian studies where hypoxia is known to increase leptin expression and circulating leptin levels (Ambriosini et al, 2002; Quintero et al, 2010), and with recent observations in adult zebrafish where chronic hypoxia increased hepatic leptin-a mRNA levels and hypoxia-inducible factor 1 stimulated the transcription of leptin-a (Chu et al, 2010). As previously observed in the liver of marine medaka [Oryzias malastigma (Wong et al, 2007)] and mice (Baze et al, 2010), hypoxia exposure in common carp also elicited significant increases in hepatic lepr expression. Although the physiological significance of this response is not known, an increase in liver leptin receptor abundance could enhance the potential contribution of leptin to the regulation of metabolism during hypoxic conditions.…”

Chronic hypoxia stimulates an enhanced response to immune challenge without evidence of an energetic tradeoff

“…This simulated altitude was closer to 4250m. Details of methods for monitoring appropriate levels of oxygen and delivering oxygen to the chambers are described in Baze et al (Baze et al, 2010). Each chamber housed up to 12 mice individually in 30ϫ8ϫ12cm standard rodent cages.…”

“…Evidence that the immune system is also affected by chronic, systemic hypoxia comes from studies at high altitude and of chronic obstructive pulmonary disease (Facco et al, 2005;McNicholas, 2009). Furthermore, despite the waning of HIF induction within hours of hypoxic exposure, studies on gene regulation and cytokine regulation suggest that the effect of hypoxia on the immune system persists over longer time scales than hours (Baze et al, 2010;Lam et al, 2008). Therefore, there is evidence to suggest that, although chronic hypoxia has little effect on circulating immune cells, it may influence gene transcription and cytokine activity, which affect immunological function.…”

Genomic insights into adaptation to high-altitude environments

“…Evidence of the action of positive selection on HIF-transcription factors in humans underscores the importance of gene regulation at high altitude, and experimental exposure to cold and hypoxia are known to have profound effects on genome-wide patterns of gene expression (Gracey et al, 2001(Gracey et al, , 2004Powell, 2003;Chen et al, 2005;Fan et al, 2005;Whitehead and Crawford, 2006;Baze et al, 2010). Thus, adaptation to high-altitude habitats may often proceed through mutations that alter gene expression phenotypes.…”