Receptores Nucleares

Mechanism of Action of Hormones That Act on Nuclear Receptors

MITCHELL A. LAZAR

Hormones can be divided into two groups on the basis of where they function in a target cell. The first group includes hormones that do not enter cells; instead, they signal by means of second messengers generated by interactions with receptors at the cell surface. All polypeptide hormones (e.g., growth hormone), monoamines (e.g., serotonin), and prostaglandins (e.g., prostaglandin E2), use cell surface receptors (see Chapter 5). The second group, the focus of this chapter, includes hormones that can enter cells. These hormones bind to intracellular receptors that function in the nucleus of the target cell to regulate gene expression. Classic hormones that use intracellular receptors include thyroid and steroid hormones.

Hormones serve as a major form of communication between different organs and tissues. They allow specialized cells in complex organisms to respond in a coordinated manner to changes in the internal and external environments. Classic endocrine hormones are secreted by endocrine glands and are distributed throughout the body through the bloodstream. These hormones were discovered by purifying the biologically active substances from clearly definable glands.

Numerous other signaling molecules share with thyroid and steroid hormones the ability to function in the nucleus to convey intercellular and environmental signals. Not all of these molecules are produced in glandular tissues. Although some signaling molecules, such as classic endocrine hormones, arrive at target tissues through the bloodstream, others have paracrine functions (i.e., acting on adjacent cells) or autocrine functions (i.e., acting on the cell of origin).

In addition to the classic steroid and thyroid hormones, lipophilic signaling molecules that use nuclear receptors include derivatives of vitamins A and D, endogenous metabolites such as oxysterols and bile acids, and non-natural chemicals encountered in the environment (i.e., xenobiotics). These molecules are referred to as nuclear receptor ligands. The nuclear receptors for all of these signaling molecules are structurally related and are collectively referred to as the nuclear receptor superfamily.1-3 The study of these receptors is a rapidly evolving field, and more detailed information can be obtained by visiting

the Nuclear Receptor Signaling Atlas web site (http://www.nursa.org [accessed September 2010]).

51

52 Mechan ism of Action of Horm ones That hat Act on Nuclear Receptors

Precursors of vitamin D are synthesized and stored

in skin and activated by ultraviolet light; vitamin D can also be derived from dietary sources. Vitamin D is then converted in the liver to 25(OH)D (25-hydroxyvitamin D, calcidiol) and in the kidney to 1,25(OH)2 D3 (1,25-dihydroxyvitamin D3, calcitriol), the most potent natural ligand of the vitamin D receptor (VDR). The 1-hydroxylation of calcidiol is tightly regulated, and calcitriol acts as a circulating hormone.

Vitamin A is stored in the liver and is activated by metabolism to all-trans-retinoic acid, which is a high-affinity ligand for retinoic acid receptors (RARs).9 Retinoic acid is likely to function as a signaling molecule in paracrine as well as endocrine pathways. Retinoic acid is also converted to its 9-cis-isomer, which is a ligand for another nuclear receptor, the retinoid X receptor (RXR).10 These retinoids and their receptors are essential for normal development of multiple organs and tissues, and they have pharmaceutical utility for conditions ranging from skin diseases to leukemia.10

Metabolic Intermediates and Products

Certain nuclear receptors respond to naturally occurring endogenous metabolic products. The peroxisome proliferator-activated receptors (PPARs) constitute the

best defined subfamily of metabolite-sensing nuclear

receptors.11 All three PPAR subtypes are activated by polyunsaturated fatty acids. No single fatty acid has particularly high affinity for any PPAR, and it is possible that these receptors function as integrators of the concentration of a number of fatty acids.

PPARα is expressed primarily in liver; the natural ligand with highest affinity for PPARα is an eicosanoid, 8(S)-hydroxyeicosatetraenoic acid,12,13 although there is evidence that the natural ligand may be a fatty acid derived from lipolysis of circulating triglyceride-rich lipoproteins.14 The fibrate class of lipid-lowering pharmaceuticals are

LIGANDS THAT ACT THROUGH NUCLEAR RECEPTORS

General Features of Nuclear

Receptor Ligands

Unlike polypeptide hormones that function through cell surface receptors, no ligands for nuclear receptors are directly encoded in the genome. All nuclear receptor ligands are small (molecular mass <1000 d) and lipophilic, enabling them to enter cells by passive diffusion, although in some cases, a membrane transport protein is involved. For example, several active and specific thyroid hormone transporters have been identified, including monocarboxylate transporter 8 (MCT8), MCT10, and organic anion transporting polypeptide 1C1 (OATP1C1).4,5 The lipophilicity of nuclear receptor ligands allows them to be absorbed from the gastrointestinal tract, facilitating their use in replacement or pharmacologic therapies for various disease states.

Another common feature of naturally occurring nuclear receptor ligands is that all are derived from dietary, environmental, or metabolic precursors. In this sense, the function of these ligands and their receptors is to translate cues from the external and internal environments into changes in gene expression. Their critical role in maintaining homeostasis in multicellular organisms is highlighted by the fact that nuclear receptors are found in all vertebrates and insects but not in single-cell organisms such as yeast.6

Because nuclear receptor ligands are lipophilic, most are readily absorbed from the gastrointestinal tract. This makes nuclear receptors excellent targets for pharmaceutical interventions. In addition to natural ligands, many drugs in clinical use target nuclear receptors, ranging from those used to treat specific hormone deficiencies to those used to treat common multigenic conditions such as inflammation, cancer, and type 2 diabetes.

Subclasses of Nuclear Receptor Ligands

One classification of nuclear receptor ligands is outlined in Table 4-1 and is described in the following paragraphs.

Classic Hormones

The classic hormones that use nuclear receptors for signaling are thyroid hormone and steroid hormones. Steroid hormones include cortisol, aldosterone, estradiol, progesterone, and testosterone. In some cases (e.g., thyroid hormone receptor α and β genes [THRA and THRB], estrogen receptor α and β genes [ESR1 and ESR2]), there are multiple receptor genes that encode multiple receptors. Multiple receptors for the same hormone can also be derived from a single gene by alternative promoter usage or by alternative splicing (e.g., THRB1 and THRB2).

Some receptors can mediate the signals of multiple hormones. For example, the mineralocorticoid receptor, also known as the aldosterone receptor or nuclear receptor 3C2 (NR3C2), has equal affinity for cortisol7 and probably functions as a glucocorticoid receptor in some tissues, such as the brain; likewise, the androgen receptor binds and responds to both testosterone and dihydrotestosterone (DHT).8

Vitamins

Vitamins are essential constituents of a healthful diet. Two fat-soluble vitamins, A and D, are precursors of important signaling molecules that function as ligands for nuclear receptors.

TABLE 4-1

Nuclear Receptor Ligands and Their Receptors

Ligand

Receptor

Classic Hormones

Thyroid hormone

Thyroid hormone receptor (TR), subtypes α, β

Estrogen

Estrogen receptor (ER), subtypes α, β

Testosterone

Androgen receptor (AR)

Progesterone

Progesterone receptor (PR)

Aldosterone

Mineralocorticoid receptor (MR)

Cortisol

Glucocorticoid receptor (GR)

Vitamins

1,25-(OH)2-Vitamin D3

Vitamin D receptor (VDR)

All-trans-retinoic acid

Retinoic acid receptor, subtypes α, β, γ

9-cis-Retinoic acid

Retinoid X receptor (RXR), subtypes α, β, γ

Metabolic Intermediates and Products

Fatty acids

Peroxisome proliferator-activated receptor (PPAR), subtypes α, δ, γ

Oxysterols

Liver X receptor (LXR), subtypes α, β

Bile acids

Bile acid receptor (BAR)

Heme

Rev-Erb subtypes α, β

Xenobiotics

??

Pregnane X receptor (PXR), constitutive androstane receptor (CAR)

Mechanism of Action of Hormones That Act on Nuclear Receptors 53

to respond to metabolites and environmental compounds

were originally discovered as orphans. Therefore, future

research will likely find that additional orphan receptors

function as receptors for physiologic, pharmacologic, or

environmental ligands. For example, the nuclear receptor

NR1D1 (formerly called Rev-Erbα), which is a regulator of

circadian rhythms,24 has been shown to be a receptor for

molecular heme,25,26 which is involved in the coordination

of circadian rhythms and metabolism.

Variant Receptors

The carboxyl-terminus of the nuclear receptors is responsible

for hormone binding. In a few nuclear receptors,

including THRA and the glucocorticoid receptor, alternative

splicing produces variant receptors with unique

C-termini that do

...