MAIN NUCLEAR RECEPTORS

Classical nuclear receptors can be expressed in the plasma membraneref.
With few exceptions, these proteins contain an :

Upon ligand-binding, nuclear receptors undergo a conformational change that coordinately dissociates corepressors and facilitates recruitment of coactivator proteins to enable transcriptional activation (see also Transcription factors in STP)
 
type
nuclear receptor name
ligand(s)
agonists
antagonists
response elements (RE) (including hormone response elements (HRE))
up-regulated genes
down-regulated genes
endocrine steroid  receptors : they bnd to DNA as homodimers, and their ligands are synthetised exclusively from endogenous endocrine sources that are regulated by negative feedback control of the hyopothalamic-pituitary axis; they bind to their receptors with high affinity (Kd = 0.01 M to 10 nM). In vertebrates, the endocrine steroid receptor system evolved to regulate a variety of crucial metabolic and developmental events, including sexual differentiation, reproduction, carbohydrate metabolism, and electrolyte balance.  glucocorticoid receptor (GR) => alternative splicing => 
  • GRa
  • GRb : the last 50 aa of GRa are replaced with a unique 15-aa sequence lacking a steroid-binding domain, hence acting as dominant inhibitor of GRa. by forming transcriptionally inactive heterodimers. This receptor is located in the nucleus regardless of ligand status, but it can also be found in the cytoplas complexed to hsp90.
cortisol
cortisone
Inhaled corticosteroids (ICS) 
  • aclometasone dipropionate (Aclovate®) (topical)
  • amcinonide (Cyclocort®) (topical)
  • beclomethasone dipropionate (BDP) (Beclovent®, Beconase AQ®, Vanceril®, ...) (inhalation) (orBec®) (oral)
  • betamethasone (Celestone®) (oral) dipropionate (Diprolene®, Diprosone®) (topical), sodium phosphate (Celestone Phosphate®, ...) (injectable), sodium phosphate and acetate (Celestone Soluspan®) (injectable) or valerate (Betatrex®, Beta-Val®, Betnovate®, Valisone®, ..) (topical)
  • budesonide (Entocort EC®) (oral) (Pulmaxan® Turbohaler®, Pulmicort® Respules®, Pulmicort® Turbuhaler®, Rhinocort®; Symbicort® in combination with formoterol) (inhalation)
  • ciclesonide (Alvesco®) (inhalation) is inactive until it reaches the lung, where it is converted to its active metabolite desisobutyryl-ciclesonide. In addition, other favourable pharmacokinetic and pharmacodynamic characteristics such as high protein binding, low oral bioavailability and rapid clearance contribute to the efficacy and improved systemic safety profile of ciclesonide.
  • clobestone butyrate 0.05% (Eumovate®) (topical)
  • clobetasol propionate (Dermovate®, Temovate®) (topical)
  • clocortolone pivalate (Cloderm®) (topical)
  • cortisol / hydrocortisone (Cortef®, Cortifoam®, 0.5% (Cutaderm®, Dilucort®, Skincalme®), 0.1% (Procutan®, Dilucort®), Hydrocortone®, Hytone®, Nutricort®, Penecort®, ...) (topical, enema, otic, oral, injectable) acetate (Hydrocortone Acetate®, ...) (topical, suppositories, rectal foam, injectable), butyrate (Locoid®) (topical), cypionate (Cortef®) (oral), sodium phosphate (Hydrocortone Phosphate®) (injectable), sodium succinate (A-Hydrocort®, Flebocortid®, Solu-Cortef®, ...) (injectable), valerate (Westcort®) (topical), or acetate (Cortone Acetate®) (oral, injectable)
  • deflazacort (Calcort®, Flantadin®) (oral)
  • desonide (Desowen®, Tridesilon®) (topical)
  • desoximetasone (Topicort®, Topicort LP®) (topical)
  • dexamethasone (DEX / DXM) (Decadron®, ...) (oral, topical) acetate (Decadron-LA®, ...) (injectable) or sodium phosphate (Decadron Phosphate®, Hexadrol Phosphate®, Luxazone®, Soldesam®, ...) (topical, ophthalmic, otic, injectable)
  • diflorasone diacetate (Florone®, Maxiflor®, Psorcon®) (topical)
  • diflucortolone valerate (Nerisone®; Travocort® in combination with isoconazole nitrate)
  • 9a-fludrocortisone acetate (Florinef®) (oral)
  • flunisolide (Aerobid®, Nasalide®) (inhalation)
  • fluocinolone acetonide (Fluonid®, Synalar®, Synalar HP®, ...) (topical)
  • fluocinonide (Lidex®, Lidex-E®, Fluonex®) (topical)
  • fluorometholone (Fluor-OP®, FML Liquifilm®) (ophthalmic)
  • flurandrenolide (Cordran®, Cordran SP®,  Halog®) (topical)
  • fluticasone propionate (FP) (Cutivate®, Flovent®; Advair®/Seretide® in combination with salmeterol) (inhalation)
  • halcinonide (Halog®, Halog-E®) (topical)
  • halobetasol propionate (Ultravate®) (topical)
  • loteprednol (ZyLet® in combination with tobramycin) (ophthalmic solution)
  • medrysone (HMS Liquifilm®) (ophthalmic)
  • 6a-methylprednisolone (Medrol®) (oral) acetate (Depo-Medrol®, Medrol Acetate®, ...) (topical, injectable), acoponate (Advantan®), or sodium succinate (A-Methapred®, Urbason®, Solu-Medrol®) (injectable)
  • mometasone (Asmanex®) (inhalation) furoate (Elocon®, Nasonex®) (topical)
  • prednisolone (Delta-Cortef®, Meticortelone®, Soludacortin®) (oral) acetate (Econopred®, ...) (ophthalmic, injectable) (side effects), methasulfobenzoate, sodium phosphate (Pediapred®, ...) (oral, ophthalmic, injectable) or tebutate (Huydeltra-T.B.A.®, ...) (injectable)
  • prednisone (PDN) (Deltasone®, Deltacortene® (5 mg), Deltacortene forte® (25 mg), ...)
  • tixocortol pivalate (Rectovalone®, Jouveinal®)
  • triamcinolone (Aristocort®, Aristocort A®,  Kenacort®) (oral) acetonide (Azmacort®, Kenalog®, Locoid®) (inhalational, topical, injectable), diacetate (Aristocort, Kenacort Diacetate, ...) (oral, injectable), or hexacetonide (Aristospan®) (injectable)
mifepristone / RU 38486 (RU 486®
As3+ (arsenite)
glucocorticoid-responsive element (GRE) : 5'-AGAACA-3' lipocortin 1  / annexin 1 (increased synthesis and externalization on cell membrane) 
PEPCK
G6Pase 
PNMT
F-2,6-bisphosphatase 
IkB => inhibition of iNOS
IL-4 (but stress levels of dexamethasone downregulate its expression in T cells) 
IL-10 (but low physiological doses suppress its expression) 
TGF-b1
IL-1RA
b2-AR (positive feedback in therapy of bronchial asthma
p57Kip2
glucocorticoid-induced leucine zipper (GILZ)
glucocorticoid-induced TNFR family related (GITR)
PXR
tyrosine hydroxylase
epithelial sodium channel (ENaC)
gamma chain fibrinogen
at transcriptional level :  at post-transcriptional level : 
mineralocorticoid receptor (MR) aldosterone (high affinity)
cortisol (low affinity)
11-deoxycorticosterone 

weak antagonists : 

[as mineralocorticoids are present at concentrations far lower than glucocorticoids and the latter have similar binding affinity, aldosterone-responsive cells also express the SCAD 11b-HSD type 2 to inactivate glucocorticoids]
spironolactone (Aldactone®) (PO) and its metabolites : 
  • canrenone 
  • potassium canrenoate (IV) (Canrenol®, Soldactone®, Soludactone®)
  • eplerenone (Inspra®)
mineralocorticoid-responsive element (MRE)
glucocorticoid-responsive element (GRE)
aldosterone-induced proteins (AIP)
estrogen receptor a (ERa) / 1 17-b-estradiol / E2 (BES) (genomic pathway for cell growth and proliferation promotion) 
increases in cyclic AMP within 15 seconds of estrogen application was reported as early as 1967ref and confirmed in 1994ref (time course was too fast to be a result of transcription, and the product was a known second messenger for receptors residing in the cell membrane). The first evidence of estrogen-specific binding sites on the membrane came in 1970ref: they function as GsPCR. Estradiol travels through the bloodstream bound to proteins, including high density lipoprotein (HDL). Now, there is evidence that HDL may actually help deliver estrogen to its receptors. HDL binds to scavenger receptors, class B type I (SR-BI), which in endothelial cells are localized to plasma membrane caveolae along with estrogen receptors and nitric oxide synthase. Smart and his colleagues demonstrated that stimulation of nitric oxide synthase occurred with HDL isolated from females but not from males and was dependent on the presence of SR-BIref. The scenario has SR-BI snagging HDL from the bloodstream and, in females, delivering estrogen to its membrane receptor to induce nitric oxide synthase and vasorelaxation. By linking two factors associated with decreased risk of cardiovascular disease, HDL levels and gender, the findings also provide a mechanism for the relative cardioprotection observed in premenopausal women. 

There is recent evidence for a mitochondrial pool of estrogen receptorsref1, ref2

There is evidence for a novel receptor called ER-Xref : receptor binding occurs at low ligand concentration and levels off when receptors are all occupied, satisfying pharmacologic requisites of affinity and saturability. Compared to ER-a, ER-X has a lower molecular weight, a greater response to 17-a-estrodiol (the typically inactive stereoisomer of 17-b-estradiol), and an opposite effect on mitogen-activated protein (MAP) kinase. Other investigators may be misidentifying ER-X as ER-a. The confusion results because antibodies to ER-a also cross-react with ER-X. There is also evidence for aestrogen receptor that is distinct from ER-a, ER-b, and ER-Xref

ER agonist-ER-ERE complex recruits steroid-receptor coactivator 1 (SRC-1) and cAMP-element binding protein (CBP : a HAT that facilitates formation of the general transcription apparatus (GTA)). 

nonsteroidal compounds 

  • diethylstilbestrol (DES) 
  • p,p'-dichlorodiphenyltrichloroethan (DDT)
  • bisphenol A
  • phytoestrogens (PE) (in soy infant formulas)
    • lignans
      • enterodiol =gut bacteria=> enterolactone
      • matairesinol
      • secoisolariciresinol
    • isoflavones
      • genistein
      • glycitein
      • daidzein =gut bacteria=>
        • equol
        • O-desmethylangolensin
      • biochanin A 
      • formononetin
      • prunetin
    • coumestans : coumestrol
  • phthalate diesters are widely used as plasticizers in the manufacture of products made of polyvinyl chloride
    • symmetrical
      • dialkylphthalates
        • di-n-butyl phthalate (DBP) 
        • di-2-ethyl phthalate
        • diisooctyl phthalate
        • dioctyl terephthalate (DOTP or DEHT)
        • dicyclohexyl phthalate (DCHP)
        • diisononyl phthalate (DINP) 
        • di(2-ethylhexyl) phthalate (DEHP)
    • asymmetrical
      • butyl benzyl phthalate (BBP) 
  • cadmium
  • alkyl esters of p-hydroxybenzoic acid (parabens)
steroidal estrogens 
  • estradiol valerate (Delestrogen®, Valergen®, ...)
  • estradiol cypionate (Deo-Estradiol Cypionate®, ...)
  • ethinyl estradiol (EE) (Estinyl®; Demulen 1/35®, Desogen®, Orthocept®; Ortho Tri-Cyclen® in combination with norgestimate; Angeliq® or Yasmin® in combination with drospirenone; Arianna®, Fedra®, Ginoden®, Harmonet®, Milvane®, Minesse®, Minulet®, Triminulet® in combination with gestodene; Dueva®, Gracial®, Mercilon®, Planum®, Practil 21®,

  • Securgin® in combination with desogestrel; Egogin 30®, Ovranet®, Evanor D®, Levlen®, Loette®, Microgynon®, Miranova®, Novogyn 21®, Trigynon®, Trinordiol® in combination with levonorgestrel; Euginon® in combination with norgestrel; Trinovum® in combination with norethisterone; Diane® in combination with cyproterone acetate
  • mestranol / 3-methyl ester of ethinyl estradiol  (in combination with norethynodrel as Enovid®; in combination with norethindrone as Ortho-Novum®
  • quinestrol (Estrovis®)
  • estrone (Wehgen®)
  • Premarin® contains several estrogens excreted in the urine of pregnant mares :
    • estrone sulfate (Estratab®)
    • equilin sulfate
ER antagonist-ER-ERE complex recruits nuclear-hormone receptor corepressor (NcoR), which further recruits histone deacetylase1 (HDAC1), inhibiting formation of GTA. 

selective estrogen receptor modulators (SERMs) (tissue-selective) : 

  • tamoxifen (TAM) citrate (Kessar®, Ledertam®, Nolvadex©, Nomafen®, Tamoxene®, Virtamox®) for bone, liver, and endometrium; although tamoxifen was designed to inhibit ER, it may act as a partial agonist in the endometrium, increasing the risk of endometrial cancer) : =liver=> 
    • N-desmethyltamoxifen
    • 4-hydroxytamoxifen (4-OHT) 
  • raloxifene hydrochloride (Evista©
  • toremifene (Acapodene©, Fareston©)
pure antiestrogens (in all tissues studied) 
  • clomiphene (Clomid©, Serophene©, ...)
    • trans-clomiphene / enclomiphene
    • cis-chlomiphene / zuclomiphene
  • ICI 182,780 / fulvestrant (Faslodex©)
  • ICI 164,384
  • EM-800
  • EM-652
  • phthalate diesters
    • butyl benzyl phthalate (BBP) > 10-4 M
  • phthalate monoesters (formed from diesters by degradation) 
    • mono-n-pentyl phthalate (MPP)
    • monocyclohexyl phthalate (MCHP)
    • monobenzyl phthalate (MBZP)
    • monoisopropyl phthalate (MIPrP)
estrogen-responsive element (ERE) : whether the activated ER is a transcription activator or repressor depends on the molecules it recruits to the promoter region of the target gene  Web resources : Estrogen Responsive Genes Database (ERGDB)

corticosteroid-binding globulin (CBG) / transcortin / SERPINA6
thyroxine-binding globulin / transthyretin / prealbumin
sex steroid-binding globulin (SSBG) / sex hormone-binding globulin
factor VII
factor XII
progesteron receptor
complement component C3

protein C
protein S
antithrombin III
PAI-1
IL-6
estrogen receptor
estrogen receptor b (ERb) / 2
progesterone receptor (A and B isoforms from alternative trascription). 'Classical' genomic progesterone receptors appear relatively late in phylogenesis, i.e. it is only in birds and mammals that they are detectable. In the different species, they mediate manifold effects regarding the differentiation of target organ functions, mainly in the reproductive system. As to progesterone secretion and serum progesterone levels, there are no great quantitative differences between men and women (at least outside the luteal phase) nor age-dependent changes in serum progesterone concentrations. Progesterone influences spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the Leydig cells. Other progesterone effects in men include those on the CNS, including blocking of gonadotropin secretion, sleep improvement, and effects on tumors in the CNS (meningioma, fibroma), as well as effects on the immune system, cardiovascular system, kidney function, adipose tissue, behavior, and respiratory system. A progestin may stimulate weight gain and appetite in men as well as in women. The detection of progesterone receptor isoforms would have a highly diagnostic value in prostate pathology (benign prostatic hypertrophy and prostate cancer). The modulation of progesterone effects on typical male targets is connected with a great pharmacodynamic variability. The reason for this is that, in men, some important effects of progesterone are mediated non-genomically through different molecular biological modes of actionref progesterone => 5a-reduced progesterone metabolites as so-called neurosteroids spironolactone
progestins / progestogens / progestagens 
  • agents similar to progesterone (pregnanes)
    • medroxyprogesterone acetate (MPA) (Depo-Provera®, Farlutal®, Provera®, Cycrin®, ...) 
    • megestrol acetate (Megace®)
  • 19-norderivatives of testosterone
    • agents similar to 19-nortestosterone (estranes)
      • 19-nortestosterone
      • norethindrone acetate (Aygestin®, Norlutin®, Nor-QD®, Micronor®; in combination with mestranol as Ortho-Novum®
      • norethynodrel (in combination with mestranol as Enovid®
      • ethynodiol diacetate
    • agents similar to norgestrel (gonanes)
      • norgestrel (Norplant System®, Ovrette®; Euginon® in combination with ethinyl estradiol)
      • levonorgestrel (LNG) (Egogin 30®, Evanor D®®, Levlen®, Loette®, Microgynon, Miranova®, Novogyn 21®, Ovranet®, Trigynon®, Trinordiol® in combination with ethinyl estradiol)
      • third-generation progestins
        • gestodene (GSD)
        • desogestrel (DSG) (Dueva®, Gracial®, Mercilon®, Planum®, Practil 21®, Securgin® in combination with ethinyl estradiol)
        • norgestimate (NGM) (Demulen 1/35®, Desogen®, Orthocept®, Ortho  Tri-Cyclen® in combination with ethinyl estradiol)
  • 17a-hydroxyprogesterone caproate (Hyalutin®)
  • drospirenone (Angeliq® or Yasmin® in combination with ethinyl estradiol)
  • tibolone (Livifen®, Xyvion®) (exerting progestogenic effects) is converted into 3 active metabolites:
    • D4 isomer (exerting progestogenic and androgenic effects)
    • 3a-hydroxytibolone 
    • 3b-hydroxytibolone (exerting progestogenic and estrogenic effects and converted to D4-tibolone).
selective progesterone receptor modulators :
  • mifepristone / RU 38486 (RU 486®; Mifeprex® in combination with misoprostol
  • ulipristal acetate (CDB 2914)
  • onapristone (ZK 98 299®)
  • asoprisnil (J 867)
  • Proellex() (CDB 4124)
  • ORG 33628 
  • ORG 31710
progesterone response elements (PRE)
androgen receptor (AR) / DHT receptor (DHTR) : the gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein dihyhdrotestosterone (DHT) > testosterone > androstenedione > DHEA > DHEA-S testosterone esters : 
  • testosterone enanathate / heptanoate (Delatestryl®, ...)
  • testosterone cypionate / cyclopentylpropionate (Depo-Testosterone®, Andronate®, ...)
  • testosterone propionate (Testosterone Propionate®, ...)
  • testosterone undecanoate (Andriol®)
17a-alkylated androgens : 
  • methyltestosterone (Oretin Methyl®, ...)
  • oxandrolone (Oxandrin®)
  • stanozolol (Winstrol®)
  • fluoxymesterone (Halotestin®)
  • 17a-ethinyl-testosterone / danazol (Danocrine®, Danol®, Sanofi®)
nandrolone decanoate (Deca-Durabolin®, Nandrabolin®, Anabolin®, Androlone®, Hybolin®, Nandrobolic®
boldenone undecenoate (Vebonol®)
spironolactone
norethisterone acetate (Noristerat®; Elleste-Duet®, Estragest TTS® or Non-Ovlon® in combination with ethinyl estradiol
gestrinone / R2323 / ethyl-nor-gestrinone 
athletes' "designer steroid" : 
  • tetrahydrogestrinone (THG)
bicalutamide (Casodex®
cyproterone acetate (CA) (Dianette®, Androcur®, Androcur Depot®, Cyprostat®; Diane® in combination with ethinyl estradiol
flutamide (Eulexin®
spironolactone (Aldactone®)
androgen response element (ARE) : consensus sequence 5'-GGA/TACANNNTGTTCT-3', similar to GRE neutral endopeptidase (NEP) 
PSA
IL-6
endocrine receptors : they function as RXR heterodimers and do not fit precisely into either the feedforward or feedback paradigms. The ligands 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.  T3receptor a / c-erbA isoform 1 (kidney, gonads, skeletal muscle and heart)
  • 3,5,3'-triiodothyronine (L-T3) (Kd = 10-10 M => relative metabolic activity = 1)
  • 3,5,3',5'-tetraiodothyronine / thyroxine (L-T4) (Kd = 10-11 M => relative metabolic activity = 0.3)
  • eprotirome (KB2115) (Karo Bio) is a thyroid hormone analogue containing two bromides that, as compared with triiodothyronine, has minimal uptake in nonhepatic tissues (TRb > TRa)ref
  • thyroid hormone or T3 response element (TRE) : T(A/G)AGGTCA  carnitine palmitoyltransferase-I (CPT-I)
    Na-K-ATPase a3
    myosin heavy chain a
    b subunit of TSH
    T3 receptor a / c-erbA isoform 2 (dominant negative; brain)
    T3 receptor b isoform 1 (liver, heart, and brain)
    T3 receptor b isoform 2 (pituitary and hypothalamus)
    VDR (skeletal muscle, monocytes, osteoblasts, osteoclasts and stromal cells, secretory epithelial and few stromal cells of human prostate, keratinocytes, stomach, enterocytes, pituitary gland, ameloblasts and odontoblasts, kidney, brain, neurosensory retina, retinal pigment epithelium, ciliary body epithelium, lens epithelium, endothelium and basal epithelium of the cornea, adipose tissue, adrenal glands, parathyroid, thyroid, uterus, trophoblast, bone marrow, breast, cartilage, epididymis, testis, skin, hair follicle, ovary, parotid) 
    In rats rVDR1 isoform (which retains intron 8 of the canonical VDR (rVDR0) during alternative splicing) shows no ligand binding activity : it forms heterodimers with rVDR0 acting as a dominant negative repressor, while doesn't form a heterodimeric complex with RXR
    1a,25-(OH)2-vitamin D3 / calcitriol (hVDR Ser205, a consensus site for casein kinase II, is modified in vivo in response to hormone) 

    calcifediol / 25-hydroxycholecalciferol (at very high concentrations) (Calderol®, Didrogyl®)

    secondary bile acid litocholic acid (LCA)

    calcipotriol / calcipotriene (Dovonex®
    paricalcitol (Zemplar®
    tacalcitol (Bonalfa®, Curatoderm®
    22-oxacalcitriol 
    EB1089 
    ZK 191784 
    1,25-dihydroxy-5,6 trans-16-ene-vitamin D3 (5,6-16D3) 
    26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3
    vitamin D response element (VDRE) : direct repeat of hexameric RGGTCA core binding motifs spaced by 3 nucleotides (DR3-type VDRE)ref . Anyway  VDREs in the natural context consist of often imperfect direct repeats : the presence of RXR not only allows the VDR to bind to imperfect direct repeats, but also increases the binding affinity for perfect direct repeats. The sequences preferentially selected by the VDR homodimer and the VDR/RXR heterodimer are the direct repeats spaced by 3 nt. Inverted palindromic arrangements spaced by 9 nucleotides (IP9-type VDRE) is found in the mouse c-fos promoter. Accessory element located adjacent to the proximal VDRE, not capable of binding to VDR, is found in in the rat 24-hydroxylase gene promoter : the corresponding site of the accessory element in the human 24-hydroxylase is a DR4-type element, and this element did not function as an accessory element CASR
    insulin receptor
    human placental lactogen (hPL)
    CYP enzymes :  cytosolic binding proteins : 
    IL-2
    IFN-g
    CYP enzymes :
    RARa retinoic acid 4-((E)-2-(5,6,7,8-tetrahydro -5,5,8,8 
    -tetramethyl-2-naphthalenyl) -1-propenyl)benzoic acid (TTNPB) 
    1st generation retinoids : 
    • retinol
    • tretinoin / all-trans-retinoic acid (ATRA) (ATRA-IV® (liposome-encapsulated), Atragen®, Retin-A®, Retin-A Micro®, Renova®, ... Vesanoid®; Velac® in combination with clindamycin)
    • alitretinoin / 9-cis-retinoic acid (Panretin®)
    • isotretinoin / 13-cis-retinoic acid (Accutane®)
    2nd generation retinoids : 
    • acitretin (Soriatane®)
    • etretinate (Tegison®) (prodrug) => etretin
    3rd generation retinoids / arotinoids : 
    • tazarotene (Tazorac®)
    • bexarotene (Targretin®)
    • motretinide (Tasmaderm®) is the ethylamide of tretinoin 
    • arotinoid ethyl ester 
    • arotinoid-free carboxylic acid 
    Ro 13-7410 
    Ro 15-1570 
    adapalene (Differin®
    rexinoids
    retinoid-responsive element (RRE) : direct repeat of two half-sites, spaced by two base pairs, with the consensus sequence 5'-T(A/G)AACTTTT(T/C)ACC(T/C)-3' CYP enzymes :  cytosolic binding proteins :  apolipoprotein(a)
    RARb retinoic acid
    RARg retinoic acid
    ecdysone receptor (EcR) (in Insects, couples with ultraspiracle, the insect homolog of RXR) 20-hydroxyecdysone CYP enzymes : 
    • 26-(OH)ase
    cytosolic binding proteins : 
    • hexamerins
    ABC transporters : 
    adopted orphan receptors : they function as heterodimers with RXR. They respond to dietaray lipids and, therefore, their concentration cannot be limited by simple negative-feedback control. They bind their lipid ligands with lower affinities compared to physiological concentrations that can be affected by dietary intake (> 1 to 10 mM). They function as lipid sensors activating a positive 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. RXRa 9-cis retinoic acid
    dietary lipids :  phytanic acid
    methoprene acid
    rexinoids
    • AGN194204
    • LG100268
    • bexarotene (Targretin®)
    The consensus sequence selected by the RXR homodimer is the GGGGTCA direct repeat spaced by 1 A residue
    RXRb 9-cis retinoic acid
    dietary lipids :  phytanic acid
    methoprene acid
    LG100268 
    RXRg 9-cis retinoic acid
    dietary lipids :  phytanic acid
    methoprene acid (insecticide derivative)
    liver X receptor a (LXR-a) (liver, adipose, kidney, intestine, lung, adrenals, and macrophages) naturally occurring oxysterols : 
    24(S)-hydroxycholesterol (brain) 
    22(R)-hydroxycholesterol (adrenal) 
    24(S),25-epoxycholesterol (liver) 
    27-hydroxycholesterol (human macrophage)
    22(S)-hydroxycholesterol 
    22(R)-hydroxysterolref
    certain unsaturated fatty acids 
    geranylgeranyl pyrophosphate 
    LG100268 
    LXRa itself 
    CYP enzymes :  cytosolic binding proteins : ABC transporters : 
    liver X receptor b (LXR-b) (ubiquitously expressed) naturally occurring oxysterols : 
    24(S)-hydroxycholesterol (brain) 
    22(R)-hydroxycholesterol (adrenal) 
    24(S),25-epoxycholesterol (liver) 
    27-hydroxycholesterol (human macrophage)
    22(S)-hydroxycholesterol 
    certain unsaturated fatty acids 
    geranylgeranyl pyrophosphate 
    LG100268 
    LXRa
    CYP enzymes :  cytosolic binding proteins :  ABC transporters : 
    constitutive androstane receptor (CAR) (liver and small intestine) xenobiotics : 
    • phenobarbital (also GABAA agonist) induces its nuclear translocation, which results in increased expression of CAR target genes since, unlike the classical, ligand-dependent nuclear receptors, CAR is an apparently constitutive transactivator
    • phenobarbital-like inducers
    • pesticide 1,4-bis[2-(3,5-dichlorpyridyloxyl)]-benzene (TCPOBOP)
    • certain androgens
    • zoxazolamine
    androstanes (inverse agonist ligands) :
    • androstanol 
    • androstenol
    CYP enzymes :  ABC transporters :
    farnesoid X receptor (FXR) / bile acid receptor / NR1H4 (enterohepatic system (liver, ileum, ...), acting as a bile acid sensor that protects the body from elevated bile acid concentrations) supraphysiological concentrations of the cholesterol precursor farnesol 
    bile acids
    • chenodeoxycholic acid
    • cholic acid
    • their respective conjugate metabolites
    LG100268 
    (E)-([tetrahydrotetramethylnaphthalenyl]propyl)benzoic acid (TTNPB)ref
    cytosolic binding proteins :  ABC transporters  small heterodimer partener (SHP) => transcriptional recpressor of the orphan nuclear receptor LRH-1
    steroid xenobiotic receptor (SXR) / pregnane X receptor (PXR) (liver and small intestine) steroids 
    • pregnane
    toxic bile acids
    xenobiotics  CYP enzymes :  ABC transporters : 
    PPAR-a (forms heterodimers with RXRa, RXRb or RXRg) (naive B cells > naive T cells) fatty acids : LTB4
    8(S)-HETE
    fibrates :
    • first generation :
      • clofibrate (Atromid-S®)
      • gemfibrozil (Lopid®)
    • second generation :
      • bezafibrate (Bezalip®)
      • ciprofibrate (Lipantil®, Modalim®)
      • fenofibrate (Tricor®)
    glitazars (also PPAR-g agonists)
    WY14,643 
    LG100268 
    LG100754 
    nafenopin 
    phthalates 
    • phthalate monoesters 
      • mono-(2-ethylhexyl)-phthalate (MEHP) 
      • monobenzyl phthalate (MBzP) 
      • mono-sec-butyl phthalate (MBuP)
    • phthalate diesters
      • diethylhexylphthalate (DEHP) => MEHP
    peroxisome proliferator response element (PPRE)-containing genes : 

    CYP enzymes :

    They catalyze w-oxidation, the final catabolic step in the clearance of PPARa ligands. 

    cytosolic binding proteins : 

    ABC transporters :  The latter 2 promote transport of fatty acids into peroxisomes, where catabolic enzymes promote b-oxidation. 

    PPAR-a
    fatty acid translocase (FAT/CD36)
    SLC27A1 / fatty acid transport protein 1 (FATP1)ref1, ref2

    apoC-III
    lactoferrin
    PPAR-b / PPAR-d / NUC1 (forms heterodimers with RXRa, RXRb or RXRg) (ubiquitously expressed) fatty acids 
    prostacyclin analogs 
    carboprostacyclin
    fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue.  ABC transporters : 
    • ABCA1 in macrophages and fibroblasts
    PPAR-g (forms heterodimers with RXRa) =alternative splicing=> 
    • PPARg1 isoform (widely expressed, including activated B and T lymphocytes)
    • PPARg2 isoform (adipocytes)
    cyclopentenone 
    PGI2 / prostacyclin (PC)
    PGJ2
    15-deoxy-D12,14-PGJ2 (15d-PGJ2) (a dehydration metabolite of PGD2
    some unsaturated fatty acids 
    LTB4
    oxidized phospholipids 
    triterpenoids
    LG100268 
    LG100754 
    LY171 833 
    phthalate monoesters : 
    • mono-(2-ethylhexyl)-phthalate (MEHP)
    • monobenzyl phthalate (MBzP) 
    • mono-sec-butyl phthalate (MBuP)
    thiazolidinediones (TZD) / glitazones : 
    • BRL49653
    • ciglitazone
    • englitazone 
    • pioglitazone (Actos®)
    • rosiglitazone (Avandia®; Avandamet® in combination with metformin)
    • troglitazone (TGZ) (Rezulin®)
    non-thiazolidinedione, tyrosine-derived analogs (TA) / glitazars (also PPAR-a agonists) : 
    • farglitazar / GI262570 /  [(S)-2-(2-benzoylphenylamino)-3- [4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl) ethoxy]phenyl]propionic acid]
    • GW7845
    • GW 1929
    • muraglitazar / BMS-298585] / N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2- (5- methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl]methyl]glycine (Pargluva®)
    • tesaglitazar (Galida®)
    a metabolite of di[2-ethylhexyl]phthalate
    telmisartan (also an AT1 antagonist)
      PPAR response element : 5'- AACTAGGNCA AAGGTCA -3' CYP enzymes  cytosolic binding proteins (promoting fat storage) :  ABC transporters : 
    • ABCA1 in macrophages via indirect mechanism involving the LXR pathway, which in turn promotes cellular efflux of phospholipids and cholesterol into HDLs 
    VEGF-A
    orphan receptors, unknown meaning steroidogenic factor 1 (SF-1) AMH
    LRH-1 CYP enzymes : 
    DAX-1 genes transactivated by SF-1
    SHP
    TLX (adult vertebrate forebrains : maintains adult neural stem cells in an undifferentiated, proliferative state by transcriptional repression, e.g. of the astrocyte marker GFAP) GFAP
    PNR
    NR4A1 / NUR77 / NGFI-Ba LG100268  NGFI-B response element (NBRE) :AGGTCA
    NR4A2 / Nur-related factor 1 (NURR1) / NGFI-Bb tyrosine hydroxylase
    NR4A3 / neuron-derived orphan receptor 1 (NOR1) / GFI-Bg
    RAR-related orphan receptor a (RORa)
    RAR-related orphan receptor b (RORb) tretinoin / all-trans-retinoic acid (ATRA) (ATRA-IV® (liposome-encapsulated), Atragen®, Retin-A®, Retin-A Micro®, Renova®, ...; Velac® in combination with clindamycin
    ALRT 1550
    RAR-related orphan receptor g (RORg)
    ERRa lactoferrin 
    osteopontin 
    medium-chain acyl coenzyme A dehydrogenase (MCAD) 
    thyroid hormone receptor
    ERRb
    ERRg (Rattus norvegicus)
    RVRa
    RVRb
    RVRg
    GCNF
    TR2
    TR4
    HNF-4
    COUP-TFa
    COUP-TFb / COUP-TFII / NR2F2 (vein endothelium)
    COUP-TFg
    aryl hydrocarbon receptor (AHR / AhR) (partner cofactor is HIF-1b / aryl hydrocarbon receptor nuclear translocator (ARNT)) LXA4 planar polycyclic or halogenated aromatic hydrocarbons :  3'-methoxy-4'-nitroflavone (MNF) 
    benzo[a]pyrene (BaP) 
    o,p'-DDT 
    a-naphthoflavone 
    b-naphthoflavone
    dioxin response elements (DRE) : core sequence 5'-TNGCGTG-3'  TGF-a
    CYP1A1
    Web resources :
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