• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Mar 15, 1993; 90(6): 2160–2164.

Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers.


The nuclear hormone receptors called PPARs (peroxisome proliferator-activated receptors alpha, beta, and gamma) regulate the peroxisomal beta-oxidation of fatty acids by induction of the acyl-CoA oxidase gene that encodes the rate-limiting enzyme of the pathway. Gel retardation and cotransfection assays revealed that PPAR alpha heterodimerizes with retinoid X receptor beta (RXR beta; RXR is the receptor for 9-cis-retinoic acid) and that the two receptors cooperate for the activation of the acyl-CoA oxidase gene promoter. The strongest stimulation of this promoter was obtained when both receptors were exposed simultaneously to their cognate activators. Furthermore, we show that natural fatty acids, and especially polyunsaturated fatty acids, activate PPARs as potently as does the hypolipidemic drug Wy 14,643, the most effective activator known so far. Moreover, we discovered that the synthetic arachidonic acid analogue 5,8,11,14-eicosatetraynoic acid is 100 times more effective than Wy 14,643 in the activation of PPAR alpha. In conclusion, our data demonstrate a convergence of the PPAR and RXR signaling pathways in the regulation of the peroxisomal beta-oxidation of fatty acids by fatty acids and retinoids.

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 (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990 Oct 18;347(6294):645–650. [PubMed]
  • Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell. 1992 Mar 6;68(5):879–887. [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]
  • Tugwood JD, Issemann I, Anderson RG, Bundell KR, McPheat WL, Green S. The mouse peroxisome proliferator activated receptor recognizes a response element in the 5' flanking sequence of the rat acyl CoA oxidase gene. EMBO J. 1992 Feb;11(2):433–439. [PMC free article] [PubMed]
  • Wahli W, Martinez E. Superfamily of steroid nuclear receptors: positive and negative regulators of gene expression. FASEB J. 1991 Jun;5(9):2243–2249. [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]
  • Hertz R, Bar-Tana J. Induction of peroxisomal beta-oxidation genes by retinoic acid in cultured rat hepatocytes. Biochem J. 1992 Jan 1;281(Pt 1):41–43. [PMC free article] [PubMed]
  • Yu VC, Delsert C, Andersen B, Holloway JM, Devary OV, När AM, Kim SY, Boutin JM, Glass CK, Rosenfeld MG. RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell. 1991 Dec 20;67(6):1251–1266. [PubMed]
  • Zhang XK, Hoffmann B, Tran PB, Graupner G, Pfahl M. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors. Nature. 1992 Jan 30;355(6359):441–446. [PubMed]
  • Marks MS, Hallenbeck PL, Nagata T, Segars JH, Appella E, Nikodem VM, Ozato K. H-2RIIBP (RXR beta) heterodimerization provides a mechanism for combinatorial diversity in the regulation of retinoic acid and thyroid hormone responsive genes. EMBO J. 1992 Apr;11(4):1419–1435. [PMC free article] [PubMed]
  • Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature. 1992 Jan 30;355(6359):446–449. [PubMed]
  • Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S, et al. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell. 1992 Jan 24;68(2):377–395. [PubMed]
  • Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG. RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors. EMBO J. 1992 Apr;11(4):1409–1418. [PMC free article] [PubMed]
  • Widom RL, Rhee M, Karathanasis SK. Repression by ARP-1 sensitizes apolipoprotein AI gene responsiveness to RXR alpha and retinoic acid. Mol Cell Biol. 1992 Aug;12(8):3380–3389. [PMC free article] [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]
  • Goldfischer S, Reddy JK. Peroxisomes (microbodies) in cell pathology. Int Rev Exp Pathol. 1984;26:45–84. [PubMed]
  • Osmundsen H, Bremer J, Pedersen JI. Metabolic aspects of peroxisomal beta-oxidation. Biochim Biophys Acta. 1991 Sep 11;1085(2):141–158. [PubMed]
  • Schreiber E, Matthias P, Müller MM, Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. [PMC free article] [PubMed]
  • Marks MS, Levi BZ, Segars JH, Driggers PH, Hirschfeld S, Nagata T, Appella E, Ozato K. H-2RIIBP expressed from a baculovirus vector binds to multiple hormone response elements. Mol Endocrinol. 1992 Feb;6(2):219–230. [PubMed]
  • Nagata T, Segars JH, Levi BZ, Ozato K. Retinoic acid-dependent transactivation of major histocompatibility complex class I promoters by the nuclear hormone receptor H-2RIIBP in undifferentiated embryonal carcinoma cells. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):937–941. [PMC free article] [PubMed]
  • de Wet JR, Wood KV, DeLuca M, Helinski DR, Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. [PMC free article] [PubMed]
  • Chen RF. Removal of fatty acids from serum albumin by charcoal treatment. J Biol Chem. 1967 Jan 25;242(2):173–181. [PubMed]
  • Berge RK, Aarsland A, Kryvi H, Bremer J, Aarsaether N. Alkylthioacetic acid (3-thia fatty acids)--a new group of non-beta-oxidizable, peroxisome-inducing fatty acid analogues. I. A study on the structural requirements for proliferation of peroxisomes and mitochondria in rat liver. Biochim Biophys Acta. 1989 Aug 22;1004(3):345–356. [PubMed]
  • Lock EA, Mitchell AM, Elcombe CR. Biochemical mechanisms of induction of hepatic peroxisome proliferation. Annu Rev Pharmacol Toxicol. 1989;29:145–163. [PubMed]
  • Smith WL. The eicosanoids and their biochemical mechanisms of action. Biochem J. 1989 Apr 15;259(2):315–324. [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]
  • Tobias LD, Hamilton JG. The effect of 5,8,11,14-eicosatetraynoic acid on lipid metabolism. Lipids. 1979 Feb;14(2):181–193. [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]
  • Flatmark T, Christiansen EN, Kryvi H. Evidence for a negative modulating effect of erucic acid on the peroxisomal beta-oxidation enzyme system and biogenesis in rat liver. Biochim Biophys Acta. 1983 Oct 11;753(3):460–466. [PubMed]
  • Hayes KC, Khosla P. Dietary fatty acid thresholds and cholesterolemia. FASEB J. 1992 May;6(8):2600–2607. [PubMed]
  • Nestel PJ. Effects of N-3 fatty acids on lipid metabolism. Annu Rev Nutr. 1990;10:149–167. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...