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The role of C. elegans NHR-49 in regulating global lipid homeostasis

Pathare, Pranali (2011) The role of C. elegans NHR-49 in regulating global lipid homeostasis. PhD thesis, University of Washington / Fred Hutchinson Cancer Research Center.

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Abstract

Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism, one of the primary energy sources in physiological settings, remain poorly understood. I chose the model organism C elegans to elucidate how nuclear receptors and their regulatory partners maintain global metabolic homeostasis and coordinate multiple signals from different tissues under different contexts to modulate the appropriate transcriptional programs. I set out to explore the impact of the C elegans lipid sensing nuclear receptor NHR-49 on global animal metabolism and physiology. Genome-wide gene expression studies revealed that NHR-49 broadly regulates target genes that fall into several physiological categories including energy balance, lipid binding, lipid degradation, sphingolipid breakdown, lipid remodeling, yolk synthesis/transfer and mitochondrial biogenesis. Worms lacking nhr-49 function display a host of phenotypes that very closely mirror its gene expression profile. I identified NHR-49 co-factors that influence NHR-49 gene regulation and demonstrated that each receptor accounts for a specific subset of NHR-49 targets. Furthermore, I used deletion mutants of these individual co-factors to delineate their specific contribution to distinct phenotypes of nhr-49-/- animals. This work has identified genes and pathways that were previously not known to be regulated by NHR-49. In addition, ultrastructural analysis revealed that NHR-49 and its partner proteins participate in the orchestration of the influx and efflux of global energy stores into and from different tissues. And, finally, I discovered a previously uncharacterized role for NHR-49 in influencing mitochondrial physiology. Taken together, my findings in C. elegans not only provide novel insights into how nuclear receptor transcriptional networks coordinate to regulate global energy metabolism but also reveal the breadth of their influence on different aspects of animal physiology.

Item Type: Thesis (PhD)
Subjects: Cellular and Organismal Processes > Cell Physiology
Cellular and Organismal Processes > Metabolism
Cellular and Organismal Processes > Genetic processes > Transcription
Depositing User: Craig Johansen
Date Deposited: 04 Oct 2011 22:47
Last Modified: 14 Feb 2012 14:44
URI: http://authors.fhcrc.org/id/eprint/500

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