The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis
- Michael A. Horner1,
- Keith Pardee2,
- Suya Liu3,
- Kirst King-Jones4,
- Gilles Lajoie3,
- Aled Edwards2,
- Henry M. Krause2 and
- Carl S. Thummel1,5
- 1Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
- 2Banting and Best Department of Medical Research, University of Toronto, Toronto Ontario M5G 1L6, Canada;
- 3UWO Biological Mass Spectrometry Laboratory, University of Western Ontario, London, Ontario N6G 2V4, Canada;
- 4Department of Biological Sciences, University of Alberta, Edmonton, Alberta T6G 2E9, Canada
Abstract
Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis.
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Footnotes
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↵5 Corresponding author.
E-MAIL carl.thummel{at}genetics.utah.edu; FAX (801) 581-5374.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1833609.
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Supplemental material is available at http://www.genesdev.org.
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- Received June 17, 2009.
- Accepted October 2, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press
