UC San Diego

High altitude studies have been insightful in revealing putative hypoxia tolerant genes to improve pathological and physiological conditions that involve hypoxia or ischemia. Whole-genome sequencing of Ethiopian highlanders identified LIPE (Lipase E, Hormone Sensitive Type), as an important gene that allows them to live in chronic low oxygen conditions (Udpa et al., 2014). Using Drosophila melanogaster, ubiquitous knockdown of the ortholog of this gene, hormone-sensitive lipase (Hsl), results in increased tolerance to chronic hypoxia. To elucidate the tissue specificity of the adaptive phenotype, UAS-RNAi(Hsl) line was crossed with different cell- or tissue-specific GAL4 drivers to systematically knockdown this gene, without altering its expression in the rest of the organism. There was a remarkable difference in eclosion rates when Hsl was knocked down in eclosion hormone-expressing neurons, third instar larval fat body, oenocytes, and hemocytes, constituting a four-fold increase over controls (all knockdown crosses were >87%, P<0.005). Since Hsl plays a prominent role in lipid metabolism, its inhibition in the cell(s) or tissue(s) that produced the most profound response to hypoxia tolerance were quantified to provide evidence of any changes in triglyceride levels. An augmented triglyceride concentration was observed in Hsl knockdown crosses, specifically in, UAS-RNAi(Hsl) x da-GAL4 and UAS-RNAi(Hsl) x Eh-GAL4 with a 1.5- to 2-fold increase in hypoxia when compared with controls. This data suggests that lipid accumulation as a result of Hsl knockdown may be biochemically significant in promoting hypoxia tolerance.