The Drosophila DHR96 Nuclear Receptor Binds Cholesterol and Regulates Cholesterol Homeostasis

Authors

Michael A. Horner, University of Utah
Keith Pardee, University of Toronto
Suya Liu, University of Western Ontario
Kirst King-Jones, University of Alberta
Gilles Lajoie, University of Western Ontario
Aled Edwards, University of Toronto
Henry M. Krause, University of Toronto
Carl S. Thummel, University of Utah

Document Type

Article

Publication Date

12-1-2009

Journal

Genes & Development

Volume

23

Issue

23

First Page

2711

Last Page

2716

URL with Digital Object Identifier

http://dx.doi.org/10.1101/gad.1833609

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.