Ce document numérisé est le fruit d'un long travail approuvé par le ...

610 Huin, Carriveau, Bianchi, Keller, Collet, Krémarik-Bauillaud, Damenjaud, Bécuwe, Schahn, Ménard, Dauça
than in duodenum. The different spatiotemporal expression
of PPARŒ, PPAR[3, and PPAR'Y during development
of the human fetal intestine and their ligand
specificity (S0rensen et al. 1998) suggest that these receptors
are involved in different intestinal functions.
PPARΠligands induce the expression of genes involved
in lipid absorption and transport in the rat
small intestine (Martin et al. 1997; Motojima et al.
1998). The physiological raIe of PPAR[3 in the small
and large intestine remains unknown. PPAR'Y ligands
have been shown to inhibit proliferation and to induce
differentiation of human colon cancer cells (Brockman
et al. 1998; Sarraf et al. 1998). On the other hand, the
same ligands enhance colon polyp and tumor formation
in the min!+ mouse model (Lefebvre et al. 1998;
Saez et al. 1998). It is evident fram our results that
PPAR'Y is expressed along the intestinal crypt-villous
region in both proliferating and differentiated cells. At
present, it is difficult to speculate about the precise
raIe played by PPAR'Y in intestinal celliife.
In summary, the spatiotemporal distribution of the
PPAR subtypes has been described during development
of the human fetal digestive tract. The different
ppARs are predominantly expressed in epithelial cells,
although their presence is also detected in nuclei of
cells of mesodermal origin. The three PPAR subtypes
exhibit different patterns of expression in relation to
the morphogenesis of the digestive tract. They are expressed
very early, suggesting that these receptors play
major raIes in the development and/or the physiology
of the digestive tract. Furthermore, the fact that PPAR'Y
is expressed at a high level whatever the region considered
(except the stomach) and the stage studied argues
for a prominent role of this receptor in human digestive
tract.
Acknowledgments
Supported by the Association de la Recherche contre le
Cancer (Contrat ARC no. 9233), the Ligue contre le Cancer
(Comité de Meuthe et Moselle), the Fondation de la Recherche
Médicale (Comité de Lorraine), and the Conseil de Recherches
Médicales du Canada.
We are grateful to W. Wahli (University of Lausanne) for
the mPPARO'/pSGS, mPPARl3!pSG5, mPPAR'Yl/PSGS, and
hPPAR'Yz/pBSIIKS+ plasmids, to M. Donner (UPRES 2402,
Nancy) for the 3T3 L1 cells, and to A. Stoekel for her skillfui
assistance.
Literature Cited
Auboeuf D, Rieusset J, Fajas L, Vallier P, Freing V, Riou JP, Laville
M, Staels B, Auwerx J, Vidal H (1997) Tissue distribution and
quantification of the expression of peroxisome proliferator-activated
receptors and liver X recepror-alpha in humans: no alteration
in adipose tissue of obese and NIDDM patients. Diabetes
46:1319-1327
Avrameas S (1969) Coupling of enzymes to protein with glutaraldehyde.
Use of the conjugates for the detection of antigens and antibodies.
Immunochemistry 6:43-52
Basque JR, Levy E, Beaulieu JF, Ménard D (1998) Apolipoproteins
in human fetal colon: immunolocalization, biogenesis, and hormonal
regulation. J Cell Biochem 7Q:354-365
Bradford MM (1976) A rapid and sensitive method for the quantification
of microgram quantities of protein urilizing the principledye
binding. Anal Biochem 72:248-254
Braissant 0, Foufelle F, Scotto C, Dauça M, Wahli W (1996) Differentiai
expression of peroxisome proliferator-activated receprors
(PPARs): tissue distribution of PPAR-a, -13, and --y in the adult
rat. Endocrinology 137:354-366
Braissant 0, Wahli W (1998) DifferentiaI expression of peroxisome
proliferator-activated receptor -a, -13, --y during rat embryonic
development. Endocrinology 139:2748-2754
Brockman JA, Gupta RA, Dubois RN (1998) Activation of PPAR-y
leads to inhibition of anchorage-independent growth of human
colorectal cancer cells. Gastroenterology 115:1049-1055
Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA (1994) Peroxisome
proliferator-activated receptor (PPAR) gamma: adiposepredominant
expression and induction early in adipocyte differentiation.
Endocrinology 135:798-800
Chomzynski P, Sacchi N (1987) Single-step method of RNA isolation
by acid guanidium thiocyanate-phenol-chloroform extraction.
Anal Biochem 162:156-159
Dauça M, Cablé S, Calvert R, Colin S, Schilt J, Leheup B, Keller JM,
Ménard D (1996) Peroxisomes and peroxisomal enzymes in the
human fetal small intestine. Biol Neonate 69:12-21
De Lomos (1977) The ultrastructure of endocrine cells in the corpus
of the stomach of human fetuses. Am J Anat 148:359-384
Desvergne B, Wahli W (1995) PPAR: a key nuclear factor in nutrient/gene
interactions? In Baeuerle P, ed. Inducible Transcription.
Vol 1. Boston, Birkhaüsser, 142-176
Dubois RN, Gupta R, Brockman J, Reddy BS, Krakow SL, Lazar
MA (1998) The nuclear eicosanoid receptor, PPAR-y, is aberrantly
expressed in colonic cancers. Cancerogenesis 19:49-53
Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz MD, Moller
DE, Berger J (1996) Molecular cloning, expression and characterization
of human peroxisome proliferator activated receptors
-YI and -Y2. Biochem Biophys Res Commun 224:431-437
Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin
R, Najib J, Fruchart JC, Deeb S, Vidal-Puig A, Plier J, Briggs
MR, Staels B, Vidal H, Auwerx J (1997) The organisation, promoter
analysis, and expression of the human PPAR gamma gene.
J Biol Chem 272:18779-18789
Fajas L, Fruchart JC, AuwerxJ (1998) PPARgamma3 mRNA: a distinct
PPARgamma mRNA subtype transcribed from an independent
promoter. FEBS Lett 438:55-60
Johns BAE (1952) Dev~lopmental changes in the oesophageal epithelium
in man. J Anat 86:431-442
Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero
PM, Westphal H, Gonzalez FJ (1995) Targeted disruption
of the Ct isoform of the peroxisome proliferator-activated
receptor gene in mice results in abolishment of the pleiotropic effects
of peroxisome proliferators. Mol Cell Biol 15:3012-3022
Lefebvre AM, Chen l, Desreumeaux P, Najib J, Fruchart JC, Geboes
K, Heyman R, Auwerx J (1998) Activation of the peroxisome
proliferator-activated receptor -y enhances the development of
colon cancer tumors in C57BLl6J-APCmin/+ mice. Nature Med
4:1053-1057
Lemberger T, Desvergne B, Wahli W (1996) Peroxisome proliferator-activated
receptors: a nuclear receptor signaling pathway in
lipid physiology. Annu Rev Cell Dev Biol 12:335-363
Levy E, Thibault L, Ménard D (1992) Intestinallipids and lipoproteins
in the human fetus: modulation by epidermal growth factor.
J Lipid Res 33:1607-1617
Mansen A, Guardiola-Diaz H, Rafter j, Branting C, Gustafsson jA
(1996) Expression of the peroxisome proliferator-activated receptor
(PPAR) in the mouse colonic mucosa. Biochem Biophys
Res Commun 222:844-851
Martin G, Schoonjans K, Lefebvre AM, Staels B, Auwerx J (1997)
Coordinate regulation of the expression of the fatty acid transport
protein and acyl-CoA synthetase genes by PPARa and
PPAR-y activators. j Biol Chem 272:28210-28217