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(Circulation Research. 2004;95:660.)
© 2004 American Heart Association, Inc.

Reviews

Nuclear Receptor Signaling in the Control of Cholesterol Homeostasis

Have the Orphans Found a Home?

Daniel S. Ory

From the Center for Cardiovascular Research, Department of Internal Medicine, and Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, Mo.

Correspondence to Daniel S. Ory, MD, Center for Cardiovascular Research, Washington University School of Medicine, Box 8086, 660 S Euclid Ave, St Louis, MO 63110. E-mail dory{at}wustl.edu

This Review is part of a thematic series on Nuclear Receptor Signaling, which includes the following articles:

Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells

Nuclear Receptor Signaling in the Control of Cholesterol Homeostasis: Have the Orphans Found a Home?

Nuclear Receptor Signaling and Cardiac Energetics
Daniel Kelly Guest Editor

Cholesterol is essential for all mammalian cells. Cellular cholesterol requirements are met through de novo synthesis and uptake of plasma lipoproteins, homeostatic responses that are transcriptionally regulated by the sterol regulatory element-binding proteins (SREBPs). To prevent cytotoxicity attributable to accumulation of excess cholesterol, liver X receptors (LXRs) and the farnesoid X receptor (FXR), together with other members of the nuclear receptor superfamily, promote the storage, transport, and catabolism of sterols and their metabolites. Members of this metabolic nuclear receptor family include receptors for oxysterols (LXRs), bile acids (CAR, FXR, and PXR), and fatty acids (PPARs). Through coordinated regulation of transcriptional programs, these nuclear receptors regulate key aspects of cellular and whole-body sterol homeostasis, including cholesterol absorption, lipoprotein synthesis and remodeling, lipoprotein uptake by peripheral tissues, reverse cholesterol transport, and bile acid synthesis and absorption. This review focuses on the nuclear receptors that are central to the lipid metabolic signaling cascades, communication between lipid metabolites and their receptors, and the role of nuclear receptors in orchestrating the complex transcriptional programs that govern cholesterol and bile acid metabolism.

Key Words: cholesterol • bile acids • lipid homeostasis • nuclear receptors • liver X receptors • farnesoid X receptor

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