Differential involvement of peroxisome-proliferator-activated receptors alpha and delta in fibrate and fatty-acid-mediated inductions of the gene encoding liver fatty-acid-binding protein in the liver and the small intestine (original) (raw)

Abstract

Liver fatty-acid-binding protein (L-FABP) is a cytoplasmic polypeptide that binds with strong affinity especially to long-chain fatty acids (LCFAs). It is highly expressed in both the liver and small intestine, where it is thought to have an essential role in the control of the cellular fatty acid (FA) flux. Because expression of the gene encoding L-FABP is increased by both fibrate hypolipidaemic drugs and LCFAs, it seems to be under the control of transcription factors, termed peroxisome-proliferator-activated receptors (PPARs), activated by fibrate or FAs. However, the precise molecular mechanism by which these regulations take place remain to be fully substantiated. Using transfection assays, we found that the different PPAR subtypes (alpha, gamma and delta) are able to mediate the up-regulation by FAs of the gene encoding L-FABP in vitro. Through analysis of LCFA- and fibrate-mediated effects on L-FABP mRNA levels in wild-type and PPARalpha-null mice, we have found that PPARalpha in the intestine does not constitute a dominant regulator of L-FABP gene expression, in contrast with what is known in the liver. Only the PPARdelta/alpha agonist GW2433 is able to up-regulate the gene encoding L-FABP in the intestine of PPARalpha-null mice. These findings demonstrate that PPARdelta can act as a fibrate/FA-activated receptor in tissues in which it is highly expressed and that L-FABP is a PPARdelta target gene in the small intestine. We propose that PPARdelta contributes to metabolic adaptation of the small intestine to changes in the lipid content of the diet.

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Selected References

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  1. Alonso S., Minty A., Bourlet Y., Buckingham M. Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol. 1986;23(1):11–22. doi: 10.1007/BF02100994. [DOI] [PubMed] [Google Scholar]
  2. Amri E. Z., Bonino F., Ailhaud G., Abumrad N. A., Grimaldi P. A. Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J Biol Chem. 1995 Feb 3;270(5):2367–2371. doi: 10.1074/jbc.270.5.2367. [DOI] [PubMed] [Google Scholar]
  3. Bass N. M., Barker M. E., Manning J. A., Jones A. L., Ockner R. K. Acinar heterogeneity of fatty acid binding protein expression in the livers of male, female and clofibrate-treated rats. Hepatology. 1989 Jan;9(1):12–21. doi: 10.1002/hep.1840090104. [DOI] [PubMed] [Google Scholar]
  4. Basu-Modak S., Braissant O., Escher P., Desvergne B., Honegger P., Wahli W. Peroxisome proliferator-activated receptor beta regulates acyl-CoA synthetase 2 in reaggregated rat brain cell cultures. J Biol Chem. 1999 Dec 10;274(50):35881–35888. doi: 10.1074/jbc.274.50.35881. [DOI] [PubMed] [Google Scholar]
  5. Berger J., Leibowitz M. D., Doebber T. W., Elbrecht A., Zhang B., Zhou G., Biswas C., Cullinan C. A., Hayes N. S., Li Y. Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem. 1999 Mar 5;274(10):6718–6725. doi: 10.1074/jbc.274.10.6718. [DOI] [PubMed] [Google Scholar]
  6. Besnard P., Mallordy A., Carlier H. Transcriptional induction of the fatty acid binding protein gene in mouse liver by bezafibrate. FEBS Lett. 1993 Jul 26;327(2):219–223. doi: 10.1016/0014-5793(93)80173-r. [DOI] [PubMed] [Google Scholar]
  7. Braissant O., Foufelle F., Scotto C., Dauça M., Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 1996 Jan;137(1):354–366. doi: 10.1210/endo.137.1.8536636. [DOI] [PubMed] [Google Scholar]
  8. Brown P. J., Smith-Oliver T. A., Charifson P. S., Tomkinson N. C., Fivush A. M., Sternbach D. D., Wade L. E., Orband-Miller L., Parks D. J., Blanchard S. G. Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. Chem Biol. 1997 Dec;4(12):909–918. doi: 10.1016/s1074-5521(97)90299-4. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Dreyer C., Keller H., Mahfoudi A., Laudet V., Krey G., Wahli W. Positive regulation of the peroxisomal beta-oxidation pathway by fatty acids through activation of peroxisome proliferator-activated receptors (PPAR). Biol Cell. 1993;77(1):67–76. doi: 10.1016/s0248-4900(05)80176-5. [DOI] [PubMed] [Google Scholar]
  11. Fan L. Q., Cattley R. C., Corton J. C. Tissue-specific induction of 17 beta-hydroxysteroid dehydrogenase type IV by peroxisome proliferator chemicals is dependent on the peroxisome proliferator-activated receptor alpha. J Endocrinol. 1998 Aug;158(2):237–246. doi: 10.1677/joe.0.1580237. [DOI] [PubMed] [Google Scholar]
  12. Glatz J. F., Börchers T., Spener F., van der Vusse G. J. Fatty acids in cell signalling: modulation by lipid binding proteins. Prostaglandins Leukot Essent Fatty Acids. 1995 Feb-Mar;52(2-3):121–127. doi: 10.1016/0952-3278(95)90010-1. [DOI] [PubMed] [Google Scholar]
  13. Gordon J. I., Alpers D. H., Ockner R. K., Strauss A. W. The nucleotide sequence of rat liver fatty acid binding protein mRNA. J Biol Chem. 1983 Mar 10;258(5):3356–3363. [PubMed] [Google Scholar]
  14. He T. C., Chan T. A., Vogelstein B., Kinzler K. W. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999 Oct 29;99(3):335–345. doi: 10.1016/s0092-8674(00)81664-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. IJpenberg A., Jeannin E., Wahli W., Desvergne B. Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA. A functional analysis of the malic enzyme gene PPAR response element. J Biol Chem. 1997 Aug 8;272(32):20108–20117. doi: 10.1074/jbc.272.32.20108. [DOI] [PubMed] [Google Scholar]
  16. 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. doi: 10.1038/347645a0. [DOI] [PubMed] [Google Scholar]
  17. Issemann I., Prince R., Tugwood J., Green S. A role for fatty acids and liver fatty acid binding protein in peroxisome proliferation? Biochem Soc Trans. 1992 Nov;20(4):824–827. doi: 10.1042/bst0200824. [DOI] [PubMed] [Google Scholar]
  18. Juge-Aubry C., Pernin A., Favez T., Burger A. G., Wahli W., Meier C. A., Desvergne B. DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5'-flanking region. J Biol Chem. 1997 Oct 3;272(40):25252–25259. doi: 10.1074/jbc.272.40.25252. [DOI] [PubMed] [Google Scholar]
  19. Kliewer S. A., Forman B. M., Blumberg B., Ong E. S., Borgmeyer U., Mangelsdorf D. J., Umesono K., Evans R. M. 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. doi: 10.1073/pnas.91.15.7355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kliewer S. A., Sundseth S. S., Jones S. A., Brown P. J., Wisely G. B., Koble C. S., Devchand P., Wahli W., Willson T. M., Lenhard J. M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4318–4323. doi: 10.1073/pnas.94.9.4318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Krey G., Braissant O., L'Horset F., Kalkhoven E., Perroud M., Parker M. G., Wahli W. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol. 1997 Jun;11(6):779–791. doi: 10.1210/mend.11.6.0007. [DOI] [PubMed] [Google Scholar]
  22. Lee S. S., Pineau T., Drago J., Lee E. J., Owens J. W., Kroetz D. L., Fernandez-Salguero P. M., Westphal H., Gonzalez F. J. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995 Jun;15(6):3012–3022. doi: 10.1128/mcb.15.6.3012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mallordy A., Besnard P., Carlier H. Research of an in vitro model to study the expression of fatty acid-binding proteins in the small intestine. Mol Cell Biochem. 1993 Jun 9;123(1-2):85–92. doi: 10.1007/BF01076478. [DOI] [PubMed] [Google Scholar]
  24. Mallordy A., Poirier H., Besnard P., Niot I., Carlier H. Evidence for transcriptional induction of the liver fatty-acid-binding-protein gene by bezafibrate in the small intestine. Eur J Biochem. 1995 Feb 1;227(3):801–807. doi: 10.1111/j.1432-1033.1995.tb20204.x. [DOI] [PubMed] [Google Scholar]
  25. Martin G., Schoonjans K., Staels B., Auwerx J. PPARgamma activators improve glucose homeostasis by stimulating fatty acid uptake in the adipocytes. Atherosclerosis. 1998 Apr;137 (Suppl):S75–S80. doi: 10.1016/s0021-9150(97)00315-8. [DOI] [PubMed] [Google Scholar]
  26. Meunier-Durmort C., Poirier H., Niot I., Forest C., Besnard P. Up-regulation of the expression of the gene for liver fatty acid-binding protein by long-chain fatty acids. Biochem J. 1996 Oct 15;319(Pt 2):483–487. doi: 10.1042/bj3190483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Murphy E. J., Prows D. R., Jefferson J. R., Schroeder F. Liver fatty acid-binding protein expression in transfected fibroblasts stimulates fatty acid uptake and metabolism. Biochim Biophys Acta. 1996 Jun 11;1301(3):191–198. doi: 10.1016/0005-2760(96)00024-0. [DOI] [PubMed] [Google Scholar]
  28. Niot I., Poirier H., Besnard P. Regulation of gene expression by fatty acids: special reference to fatty acid-binding protein (FABP). Biochimie. 1997 Feb-Mar;79(2-3):129–133. doi: 10.1016/s0300-9084(97)81504-0. [DOI] [PubMed] [Google Scholar]
  29. Peters J. M., Lee S. S., Li W., Ward J. M., Gavrilova O., Everett C., Reitman M. L., Hudson L. D., Gonzalez F. J. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta). Mol Cell Biol. 2000 Jul;20(14):5119–5128. doi: 10.1128/mcb.20.14.5119-5128.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Poirier H., Braissant O., Niot I., Wahli W., Besnard P. 9-cis-retinoic acid enhances fatty acid-induced expression of the liver fatty acid-binding protein gene. FEBS Lett. 1997 Aug 4;412(3):480–484. doi: 10.1016/s0014-5793(97)00830-2. [DOI] [PubMed] [Google Scholar]
  31. Poirier H., Niot I., Degrace P., Monnot M. C., Bernard A., Besnard P. Fatty acid regulation of fatty acid-binding protein expression in the small intestine. Am J Physiol. 1997 Aug;273(2 Pt 1):G289–G295. doi: 10.1152/ajpgi.1997.273.2.G289. [DOI] [PubMed] [Google Scholar]
  32. Richieri G. V., Ogata R. T., Kleinfeld A. M. Equilibrium constants for the binding of fatty acids with fatty acid-binding proteins from adipocyte, intestine, heart, and liver measured with the fluorescent probe ADIFAB. J Biol Chem. 1994 Sep 30;269(39):23918–23930. [PubMed] [Google Scholar]
  33. Schoonjans K., Staels B., Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 1996 May;37(5):907–925. [PubMed] [Google Scholar]
  34. Simon T. C., Roth K. A., Gordon J. I. Use of transgenic mice to map cis-acting elements in the liver fatty acid-binding protein gene (Fabpl) that regulate its cell lineage-specific, differentiation-dependent, and spatial patterns of expression in the gut epithelium and in the liver acinus. J Biol Chem. 1993 Aug 25;268(24):18345–18358. [PubMed] [Google Scholar]
  35. Spiegelman B. M., Flier J. S. Adipogenesis and obesity: rounding out the big picture. Cell. 1996 Nov 1;87(3):377–389. doi: 10.1016/s0092-8674(00)81359-8. [DOI] [PubMed] [Google Scholar]
  36. Sweetser D. A., Birkenmeier E. H., Hoppe P. C., McKeel D. W., Gordon J. I. Mechanisms underlying generation of gradients in gene expression within the intestine: an analysis using transgenic mice containing fatty acid binding protein-human growth hormone fusion genes. Genes Dev. 1988 Oct;2(10):1318–1332. doi: 10.1101/gad.2.10.1318. [DOI] [PubMed] [Google Scholar]
  37. Wolfrum C., Buhlmann C., Rolf B., Börchers T., Spener F. Variation of liver-type fatty acid binding protein content in the human hepatoma cell line HepG2 by peroxisome proliferators and antisense RNA affects the rate of fatty acid uptake. Biochim Biophys Acta. 1999 Feb 25;1437(2):194–201. doi: 10.1016/s1388-1981(99)00008-6. [DOI] [PubMed] [Google Scholar]
  38. Wolfrum C., Ellinghaus P., Fobker M., Seedorf U., Assmann G., Börchers T., Spener F. Phytanic acid is ligand and transcriptional activator of murine liver fatty acid binding protein. J Lipid Res. 1999 Apr;40(4):708–714. [PubMed] [Google Scholar]
  39. Xu H. E., Lambert M. H., Montana V. G., Parks D. J., Blanchard S. G., Brown P. J., Sternbach D. D., Lehmann J. M., Wisely G. B., Willson T. M. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell. 1999 Mar;3(3):397–403. doi: 10.1016/s1097-2765(00)80467-0. [DOI] [PubMed] [Google Scholar]