Nuclear Receptors and Lipid Physiology: Opening the X-Files

American Association for the Advancement of Science (AAAS) - Tập 294 Số 5548 - Trang 1866-1870 - 2001
Ajay Chawla1, Joyce J. Repa2, Ronald M. Evans1, David J. Mangelsdorf2
1Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, Post Office Box 85800, San Diego, CA 92186–5800, USA.
2Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9050, USA.

Tóm tắt

Cholesterol, fatty acids, fat-soluble vitamins, and other lipids present in our diets are not only nutritionally important but serve as precursors for ligands that bind to receptors in the nucleus. To become biologically active, these lipids must first be absorbed by the intestine and transformed by metabolic enzymes before they are delivered to their sites of action in the body. Ultimately, the lipids must be eliminated to maintain a normal physiological state. The need to coordinate this entire lipid-based metabolic signaling cascade raises important questions regarding the mechanisms that govern these pathways. Specifically, what is the nature of communication between these bioactive lipids and their receptors, binding proteins, transporters, and metabolizing enzymes that links them physiologically and speaks to a higher level of metabolic control? Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work. Nuclear receptors function as ligand-activated transcription factors that regulate the expression of target genes to affect processes as diverse as reproduction, development, and general metabolism. These proteins were first recognized as the mediators of steroid hormone signaling and provided an important link between transcriptional regulation and physiology. In the mid-1980s, the steroid receptors were cloned and found to exhibit extensive sequence similarity. The subsequent cloning of other receptor genes led to the unexpected discovery that there were many more nuclear receptor–like genes than previously suspected. Today, the human genome is reported to contain 48 members of this transcription factor family (1). This superfamily includes not only the classic endocrine receptors that mediate the actions of steroid hormones, thyroid hormones, and the fat-soluble vitamins A and D (2), but a large number of so-called orphan nuclear receptors, whose ligands, target genes, and physiological functions were initially unknown (3). Exciting progress has been made over the last several years to elucidate the role of these orphan receptors in animal biology. Here we review recent discoveries that suggest that unlike the classic endocrine nuclear hormone receptors, many of the orphan receptors function as lipid sensors that respond to cellular lipid levels and elicit gene expression changes to ultimately protect cells from lipid overload. The structural organization of nuclear receptors is similar despite wide variation in ligand sensitivity ( Fig. 1 ). With few exceptions, these proteins contain an NH 2 -terminal region that harbors a ligand-independent transcriptional activation function (AF-1); a core DNA-binding domain, containing two highly conserved zinc finger motifs that target the receptor to specific DNA sequences known as hormone response elements; a hinge region that permits protein flexibility to allow for simultaneous receptor dimerization and DNA binding; and a large COOH-terminal region that encompasses the ligand-binding domain, dimerization interface, and a ligand-dependent activation function (AF-2). Upon ligand binding, nuclear receptors undergo a conformational change that coordinately dissociates corepressors and facilitates recruitment of coactivator proteins to enable transcriptional activation (4). The importance of nuclear receptors in maintaining the normal physiological state is illustrated by the enormous pharmacopoeia that has been developed to combat disorders that have inappropriate nuclear receptor signaling as a key pathological determinant. These disorders affect every field of medicine, including reproductive biology, inflammation, cancer, diabetes, cardiovascular disease, and obesity. Therefore, to maintain a normal physiological state, the spatial and temporal activity of nuclear receptors must be tightly controlled by tissue-specific expression of the receptors, as well as ligand availability. Interestingly, an evaluation of the pathways involved in ligand availability reveals the existence of two distinctly different nuclear receptor paradigms. The first paradigm is represented by the classic nuclear steroid hormone receptors ( Fig. 1 ). Members of this group include the glucocorticoid (GR), mineralocorticoid (MR), estrogen (ER), androgen (AR), and progesterone (PR) receptors. Steroid receptors bind to DNA as homodimers, and their ligands are synthesized exclusively from endogenous endocrine sources that are regulated by negative-feedback control of the hypothalamic-pituitary axis (5). After synthesis, steroid hormones are circulated in the body to their target tissues where they bind to their receptors with high affinity (dissociation constant K d = 0.01 to 10 nM). In vertebrates, the steroid receptor system evolved to regulate a variety of crucial metabolic and developmental events, including sexual differentiation, reproduction, carbohydrate metabolism, and electrolyte balance. The endocrine steroid receptors, their ligands, and the pathways they regulate have been the subject of decades of research, and their mechanism of action is well documented (5). The second nuclear receptor paradigm is represented by the adopted orphan nuclear receptors that function as heterodimers with the retinoid X receptor (RXR) ( Fig. 1 ). Orphan receptors become adopted when they are shown to bind a physiological ligand. In contrast to the endocrine steroid receptors, the adopted orphan receptors respond to dietary lipids and, therefore, their concentrations cannot be limited by simple negative-feedback control ( Fig. 2 ). Members of this group include receptors for fatty acids (PPARs), oxysterols (LXRs), bile acids (FXR), and xenobiotics [steroid xenobiotic receptor/pregnane X receptor (SXR/PXR) and constitutive androstane receptor (CAR)]. Furthermore, the receptors in this group bind their lipid ligands with lower affinities comparable to physiological concentrations that can be affected by dietary intake (>1 to 10 μM). An emerging theme regarding these receptors is that they function as lipid sensors. In keeping with this notion, ligand binding to each of these receptors activates a feedforward, metabolic cascade that maintains nutrient lipid homeostasis by governing the transcription of a common family of genes involved in lipid metabolism, storage, transport, and elimination. In addition to the adopted orphan receptors, there are four other RXR heterodimer receptors that do not fit precisely into either the feedforward or feedback paradigms mentioned. These include the thyroid hormone (TR), retinoic acid (RAR), vitamin D (VDR), and ecdysone (EcR) receptors (6–9). The ligands for these four receptors and the pathways they regulate employ elements of both the endocrine and lipid-sensing receptor pathways. For example, like other RXR heterodimer ligands, both retinoic acid and ecdysone are derived from essential dietary lipids (vitamin A and cholesterol, respectively), yet they are not calorigenic and the transcriptional pathways that these ligands regulate (i.e., morphogenesis and development) more closely resemble those of the endocrine receptors. Likewise, vitamin D and thyroid hormone require exogenous elements for their synthesis (sunshine for vitamin D, iodine for thyroid hormone), yet the ultimate synthesis of these hormones and the pathways they regulate are under strict endocrine control. Thus, it is possible that these four receptors provide an evolutionary segue, spanning the gap between the endocrine receptors and the adopted orphan receptors that have recently been shown to be lipid sensors.

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Owing to space constaints numerous primary references could not be cited directly but instead were included in other review articles cited in the text. We acknowledge R. Yu and A. Shulman for helpful comments on the manuscript E. Stevens for administrative assistance and J. Simon for the graphic artwork. R.M.E. and D.J.M. are investigators and J.J.R. is an associate of the Howard Hughes Medical Institute (HHMI). R.M.E. is the March of Dimes Chair of Molecular and Developmental Biology. A.C. is a recipient of a HHMI Postdoctoral Fellowship for Physicians. Supported by HHMI the Human Frontier Science Program and the Robert A. Welch Foundation.

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American Association for the Advancement of Science (AAAS)

Tập 294 Số 5548

1866-1870

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