Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas.
OBJECTIVE
Peroxisome proliferator-activated receptor (PPAR) ligands, widely used in type 2 diabetes treatment, have variably been shown to promote or prevent colon tumor formation in animal models and cell lines, but their role in normal human colon is unknown. The aim of this study was to determine PPAR expression and function in normal human colonic epithelial cells and tubular adenomas.


METHODS
Short-term cultures of normal human colonic epithelial cells were established from biopsies obtained in 42 patients with normal colonoscopy. PPAR and adipophilin mRNA expression was assessed by real-time RT-PCR. PPARs were activated by ligands for PPAR alpha (Wy-14643), PPAR delta (GW-501516) and PPAR gamma (rosiglitazone or troglitazone). Cell viability was measured using the methyltetrazoleum assay, proliferation by thymidine incorporation, and DNA profiles by flow cytometry. PPAR mRNA levels in tubular adenomas or metaplastic polyps (n=12) were compared with those in controls.


RESULTS
PPAR alpha and gamma were consistently expressed in normal colonocytes while no PPAR delta expression could be detected. PPAR gamma activation induced a 7.5-fold increase in adipophilin expression (a PPAR-activated gene). PPAR gamma activation had no effect on viability or DNA profiles, but led to a 25% significant decrease in cell proliferation. Finally, a selective and significant 2.5-fold decrease in PPAR alpha expression was observed in tubular adenomas, but not in metaplastic polyps, compared to controls.


CONCLUSIONS
Our findings support the view that PPAR gamma ligands act as anti-proliferative agents rather than as promoters of tumorigenesis in normal human colon. Moreover, they raise interest in investigation of PPAR alpha as a therapeutic target to prevent adenoma formation.
Matthiessen
Mads Wichmann
MW
Department of Medical Gastroenterology C112, Herlev University Hospital, 2730 Herlev, Denmark.
Pedersen
Gitte
G
Albrektsen
Tatjana
T
Adamsen
Sven
S
Fleckner
Jan
J
Brynskov
Jørn
J
D000236:Adenoma / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D003106:Colon; D003110:Colonic Neoplasms / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D047492:Peroxisome Proliferator-Activated Receptors / Q000096:biosynthesis*
D047492:Peroxisome Proliferator-Activated Receptors