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 . With few exceptions, these proteins contain an NH₂-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 …