Defense Date

2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biochemistry

First Advisor

Keith Baker

Abstract

In multicellular organism, bioenergetic metabolism is strictly regulated toward efficient generation of ATP. However, in certain situations, such as in limiting oxygen or in the rapidly proliferating system like growing juvenile or cancer cells, organisms apply the metabolic strategy that favors the production of biomass (e.g., nucleotides, amino acids, and lipids) over efficiency of ATP generation. The conserved estrogen-related receptors (ERRs) are master regulators in controlling metabolic homeostasis, and good candidates for mediating the metabolic transition induced by hypoxia and development. First, we investigate how dERR influences hypoxic adaptation in Drosophila melanogaster. We find that dERR is required for a competent hypoxic response alone, or together with hypoxia inducible factor (HIF), which is the main transcription factor modulating the hypoxic adaptation. We show that dERR binds to dHIFα and participates in the HIF-dependent transcriptional program in hypoxia. In addition, dERR acts in the absence of dHIFα in hypoxia and a significant portion of HIF-independent transcriptional responses can be attributed to dERR actions, including up-regulation of glycolytic transcripts. These results indicate that competent hypoxic responses arise from complex interactions between HIF-dependent and -independent mechanisms, and that dERR plays a central role in both of these programs. Secondly, we examine how dERR modulates metabolic transition toward the fatty acid oxidation at late L3 larva stage. We show that dERR is essential for the expression of an uncharacterized long-chain-fatty-acid acyl-CoA synthetase, CG4500, which is subject to induction by starvation. Furthermore, late L3 larvae of dERR mutants exhibit altered lipid profiles with elevated medium-chain and long-chain fatty acids. Together, with the previous finding that ERR directs an early switch toward glycolysis in the embryo, our studies indicate that ERR is a master regulator of programmed metabolic shifts through Drosophila development.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-11-2013

Available for download on Tuesday, December 11, 2018

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