• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of mbcLink to Publisher's site
Mol Biol Cell. Aug 1996; 7(8): 1153–1166.
PMCID: PMC275969

Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR.

Abstract

RXR is a nuclear receptor that plays a central role in cell signaling by pairing with a host of other receptors. Previously, 9-cis-retinoic acid (9cRA) was defined as a potent RXR activator. Here we describe a unique RXR effector identified from organic extracts of bovine serum by following RXR-dependent transcriptional activity. Structural analyses of material in active fractions pointed to the saturated diterpenoid phytanic acid, which induced RXR-dependent transcription at concentrations between 4 and 64 microM. Although 200 times more potent than phytanic acid, 9cRA was undetectable in equivalent amounts of extract and cannot be present at a concentration that could account for the activity. Phytanic acid, another phytol metabolite, was synthesized and stimulated RXR with a potency and efficacy similar to phytanic acid. These metabolites specifically displaced [3H]-9cRA from RXR with Ki values of 4 microM, indicating that their transcriptional effects are mediated by direct receptor interactions. Phytol metabolites are compelling candidates for physiological effectors, because their RXR binding affinities and activation potencies match their micromolar circulating concentrations. Given their exclusive dietary origin, these chlorophyll metabolites may represent essential nutrients that coordinate cellular metabolism through RXR-dependent signaling pathways.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • AAES-JORGENSEN E. Essential fatty acids. Physiol Rev. 1961 Jan;41:1–51. [PubMed]
  • Allegretto EA, McClurg MR, Lazarchik SB, Clemm DL, Kerner SA, Elgort MG, Boehm MF, White SK, Pike JW, Heyman RA. Transactivation properties of retinoic acid and retinoid X receptors in mammalian cells and yeast. Correlation with hormone binding and effects of metabolism. J Biol Chem. 1993 Dec 15;268(35):26625–26633. [PubMed]
  • Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P, et al. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):30–34. [PMC free article] [PubMed]
  • Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science. 1987 Jul 17;237(4812):268–275. [PubMed]
  • Banner CD, Göttlicher M, Widmark E, Sjövall J, Rafter JJ, Gustafsson JA. A systematic analytical chemistry/cell assay approach to isolate activators of orphan nuclear receptors from biological extracts: characterization of peroxisome proliferator-activated receptor activators in plasma. J Lipid Res. 1993 Sep;34(9):1583–1591. [PubMed]
  • Baxter JH, Milne GW. Phytenic acid: identification of five isomers in chemical and biological products of phytol. Biochim Biophys Acta. 1969 Mar 4;176(2):265–277. [PubMed]
  • Berger TS, Parandoosh Z, Perry BW, Stein RB. Interaction of glucocorticoid analogues with the human glucocorticoid receptor. J Steroid Biochem Mol Biol. 1992 Mar;41(3-8):733–738. [PubMed]
  • Bergström S. The prostaglandins. Recent Prog Horm Res. 1966;22:153–175. [PubMed]
  • Billimoria JD, Clemens ME, Gibberd FB, Whitelaw MN. Metabolism of phytanic acid in Refsum's disease. Lancet. 1982 Jan 23;1(8265):194–196. [PubMed]
  • BLIGH EG, DYER WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):911–917. [PubMed]
  • Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA. Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties. J Med Chem. 1994 Feb 4;37(3):408–414. [PubMed]
  • Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA, et al. Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. J Med Chem. 1995 Aug 4;38(16):3146–3155. [PubMed]
  • Bruenger E, Rilling HC. Determination of isopentenyl diphosphate and farnesyl diphosphate in tissue samples with a comment on secondary regulation of polyisoprenoid biosynthesis. Anal Biochem. 1988 Sep;173(2):321–327. [PubMed]
  • Buck J, Derguini F, Levi E, Nakanishi K, Hämmerling U. Intracellular signaling by 14-hydroxy-4,14-retro-retinol. Science. 1991 Dec 13;254(5038):1654–1656. [PubMed]
  • Chen C, Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. [PMC free article] [PubMed]
  • Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. [PubMed]
  • Derguini F, Nakanishi K, Hämmerling U, Chua R, Eppinger T, Levi E, Buck J. 13,14-Dihydroxy-retinol, a new bioactive retinol metabolite. J Biol Chem. 1995 Aug 11;270(32):18875–18880. [PubMed]
  • Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. [PubMed]
  • Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell. 1995 Jun 2;81(5):687–693. [PubMed]
  • Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995 Dec 1;83(5):803–812. [PubMed]
  • Forman BM, Umesono K, Chen J, Evans RM. Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell. 1995 May 19;81(4):541–550. [PubMed]
  • Giguère V, Hollenberg SM, Rosenfeld MG, Evans RM. Functional domains of the human glucocorticoid receptor. Cell. 1986 Aug 29;46(5):645–652. [PubMed]
  • Giguere V, Ong ES, Segui P, Evans RM. Identification of a receptor for the morphogen retinoic acid. Nature. 1987 Dec 17;330(6149):624–629. [PubMed]
  • Glass CK. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev. 1994 Jun;15(3):391–407. [PubMed]
  • Göttlicher M, Widmark E, Li Q, Gustafsson JA. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4653–4657. [PMC free article] [PubMed]
  • Green S, Chambon P. A superfamily of potentially oncogenic hormone receptors. Nature. 1986 Dec 18;324(6098):615–617. [PubMed]
  • HAM RG. Albumin replacement by fatty acids in clonal growth of mammalian cells. Science. 1963 May 17;140(3568):802–803. [PubMed]
  • Harmon MA, Boehm MF, Heyman RA, Mangelsdorf DJ. Activation of mammalian retinoid X receptors by the insect growth regulator methoprene. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):6157–6160. [PMC free article] [PubMed]
  • Herbomel P, Bourachot B, Yaniv M. Two distinct enhancers with different cell specificities coexist in the regulatory region of polyoma. Cell. 1984 Dec;39(3 Pt 2):653–662. [PubMed]
  • Herndon JH, Jr, Steinberg D, Uhlendorf BW, Fales HM. Refsum's disease: characterization of the enzyme defect in cell culture. J Clin Invest. 1969 Jun;48(6):1017–1032. [PMC free article] [PubMed]
  • Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992 Jan 24;68(2):397–406. [PubMed]
  • Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2160–2164. [PMC free article] [PubMed]
  • Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7355–7359. [PMC free article] [PubMed]
  • Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995 Dec 1;83(5):813–819. [PubMed]
  • Kliewer SA, Umesono K, Heyman RA, Mangelsdorf DJ, Dyck JA, Evans RM. Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1448–1452. [PMC free article] [PubMed]
  • Koelle MR, Talbot WS, Segraves WA, Bender MT, Cherbas P, Hogness DS. The Drosophila EcR gene encodes an ecdysone receptor, a new member of the steroid receptor superfamily. Cell. 1991 Oct 4;67(1):59–77. [PubMed]
  • Kojima R, Fujimori T, Kiyota N, Toriya Y, Fukuda T, Ohashi T, Sato T, Yoshizawa Y, Takeyama K, Mano H, et al. In vivo isomerization of retinoic acids. Rapid isomer exchange and gene expression. J Biol Chem. 1994 Dec 23;269(51):32700–32707. [PubMed]
  • Lehmann JM, Jong L, Fanjul A, Cameron JF, Lu XP, Haefner P, Dawson MI, Pfahl M. Retinoids selective for retinoid X receptor response pathways. Science. 1992 Dec 18;258(5090):1944–1946. [PubMed]
  • Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A, et al. 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature. 1992 Jan 23;355(6358):359–361. [PubMed]
  • Lough AK. Blood lipids. 4. The isolation of 3,7,11,15-tetramethylhexadecanoic acid (phytanic acid) from ox-plasma lipids. Biochem J. 1964 Jun;91(3):584–588. [PMC free article] [PubMed]
  • Lough AK. The phytanic acid content of the lipids of bovine tissues and milk. Lipids. 1977 Jan;12(1):115–119. [PubMed]
  • Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, Evans RM. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev. 1992 Mar;6(3):329–344. [PubMed]
  • Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995 Dec 15;83(6):841–850. [PubMed]
  • Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. [PubMed]
  • Mangelsdorf DJ, Umesono K, Kliewer SA, Borgmeyer U, Ong ES, Evans RM. A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR. Cell. 1991 Aug 9;66(3):555–561. [PubMed]
  • Mize CE, Avigan J, Baxter JH, Fales HM, Steinberg D. Metabolism of phytol-U-14C and phytanic acid-U-14C in the rat. J Lipid Res. 1966 Sep;7(5):692–697. [PubMed]
  • Mize CE, Herndon JH, Jr, Blass JP, Milne GW, Follansbee C, Laudat P, Steinberg D. Localization of the oxidative defect in phytanic acid degradation in patients with Refsum's disease. J Clin Invest. 1969 Jun;48(6):1033–1040. [PMC free article] [PubMed]
  • MOHRHAUER H, HOLMAN RT. THE EFFECT OF DOSE LEVEL OF ESSENTIAL FATTY ACIDS UPON FATTY ACID COMPOSITION OF THE RAT LIVER. J Lipid Res. 1963 Apr;4:151–159. [PubMed]
  • Napoli JL, Pramanik BC, Williams JB, Dawson MI, Hobbs PD. Quantification of retinoic acid by gas-liquid chromatography-mass spectrometry: total versus all-trans-retinoic acid in human plasma. J Lipid Res. 1985 Mar;26(3):387–392. [PubMed]
  • O'Malley BW. Did eucaryotic steroid receptors evolve from intracrine gene regulators? Endocrinology. 1989 Sep;125(3):1119–1120. [PubMed]
  • O'Malley BW, Conneely OM. Orphan receptors: in search of a unifying hypothesis for activation. Mol Endocrinol. 1992 Sep;6(9):1359–1361. [PubMed]
  • Ong DE. Cellular retinoid-binding proteins. Arch Dermatol. 1987 Dec;123(12):1693–1695a. [PubMed]
  • Perlmann T, Jansson L. A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev. 1995 Apr 1;9(7):769–782. [PubMed]
  • Petkovich M, Brand NJ, Krust A, Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987 Dec 3;330(6147):444–450. [PubMed]
  • Pijnappel WW, Hendriks HF, Folkers GE, van den Brink CE, Dekker EJ, Edelenbosch C, van der Saag PT, Durston AJ. The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification. Nature. 1993 Nov 25;366(6453):340–344. [PubMed]
  • Repa JJ, Hanson KK, Clagett-Dame M. All-trans-retinol is a ligand for the retinoic acid receptors. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7293–7297. [PMC free article] [PubMed]
  • Samuels HH, Stanley F, Casanova J. Depletion of L-3,5,3'-triiodothyronine and L-thyroxine in euthyroid calf serum for use in cell culture studies of the action of thyroid hormone. Endocrinology. 1979 Jul;105(1):80–85. [PubMed]
  • Case records of the Massachusetts General Hospital. Normal reference laboratory values. N Engl J Med. 1980 Jan 3;302(1):37–48. [PubMed]
  • Seed B, Sheen JY. A simple phase-extraction assay for chloramphenicol acyltransferase activity. Gene. 1988 Jul 30;67(2):271–277. [PubMed]
  • Shih W, Mears T, Bradley DJ, Parandoosh Z, Weinberger C. An adenoviral vector system for functional identification of nuclear receptor ligands. Mol Endocrinol. 1991 Feb;5(2):300–309. [PubMed]
  • Sladek FM, Zhong WM, Lai E, Darnell JE., Jr Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev. 1990 Dec;4(12B):2353–2365. [PubMed]
  • Song C, Kokontis JM, Hiipakka RA, Liao S. Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10809–10813. [PMC free article] [PubMed]
  • Spector AA, John K, Fletcher JE. Binding of long-chain fatty acids to bovine serum albumin. J Lipid Res. 1969 Jan;10(1):56–67. [PubMed]
  • Steinberg D, Avigan J, Mize C, Eldjarn L, Try K, Refsum S. Conversion of U-C14-phytol to phytanic acid and its oxidation in heredopathia atactica polyneuritiformis. Biochem Biophys Res Commun. 1965 Jun 9;19(6):783–789. [PubMed]
  • Steinberg D, Avigan J, Mize CE, Baxter JH, Cammermeyer J, Fales HM, Highet PF. Effects of dietary phytol and phytanic acid in animals. J Lipid Res. 1966 Sep;7(5):684–691. [PubMed]
  • Steinberg D, Mize CE, Avigan J, Fales HM, Eldjarn L, Try K, Stokke O, Refsum S. Studies on the metabolic error in Refsum's disease. J Clin Invest. 1967 Mar;46(3):313–322. [PMC free article] [PubMed]
  • Sucov HM, Murakami KK, Evans RM. Characterization of an autoregulated response element in the mouse retinoic acid receptor type beta gene. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5392–5396. [PMC free article] [PubMed]
  • Tang GW, Russell RM. 13-cis-retinoic acid is an endogenous compound in human serum. J Lipid Res. 1990 Feb;31(2):175–182. [PubMed]
  • Teboul M, Enmark E, Li Q, Wikström AC, Pelto-Huikko M, Gustafsson JA. OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2096–2100. [PMC free article] [PubMed]
  • Umesono K, Murakami KK, Thompson CC, Evans RM. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell. 1991 Jun 28;65(7):1255–1266. [PubMed]
  • Wang LH, Tsai SY, Cook RG, Beattie WG, Tsai MJ, O'Malley BW. COUP transcription factor is a member of the steroid receptor superfamily. Nature. 1989 Jul 13;340(6229):163–166. [PubMed]
  • Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 1995 May 1;9(9):1033–1045. [PubMed]
  • Yao TP, Forman BM, Jiang Z, Cherbas L, Chen JD, McKeown M, Cherbas P, Evans RM. Functional ecdysone receptor is the product of EcR and Ultraspiracle genes. Nature. 1993 Dec 2;366(6454):476–479. [PubMed]
  • Yamamoto KR. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet. 1985;19:209–252. [PubMed]

Articles from Molecular Biology of the Cell are provided here courtesy of American Society for Cell Biology

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...