Regulation of alpha 2A-adrenergic receptor expression in the human colon carcinoma cell line HT29: SCFA-induced enterocytic differentiation results in an inhibition of alpha 2C10 gene transcription.
Previous studies on the intestinal epithelium from various species have shown that the number of alpha 2-adrenergic receptors in immature cells from the crypts is several-fold higher than in mature cells from the villi, thus suggesting an inverse relationship between enterocytic differentiation and the expression of this inhibitory receptor. The receptor density along the surface-crypt axis of the human colonic mucosa is correlated with the amount of alpha 2C10 mRNA; however, the mechanisms underlying this regulation remain unknown. The human colonic adenocarcinoma cell line HT29, which expresses the alpha 2A-adrenergic receptor and is able to undergo enterocytic differentiation, is a suitable model with which to investigate this question in vitro. In this study, we explored the effects of short chain fatty acids (SCFAs), differentiating agents normally present in the colon lumen, on alpha 2-adrenergic receptor expression. Exposure of HT29 cells to butyrate and propionate, but not acetate, resulted in a large diminution of [3H]RX821002 binding sites. The reduction of alpha 2-adrenergic receptor number induced by butyrate or propionate was due to decreased amounts of alpha 2C10 mRNA and was associated with an increase of alkaline phosphatase activity, which reflected the emergence of a more differentiated phenotype. The changes in alpha 2C10 mRNA level induced by both SCFAs were dose-dependent, rapid, and reversible and resulted from a diminution in the transcription rate of the alpha 2C10 gene. Finally, these effects were mimicked by trichostatin A, indicating that they are triggered primarily through inhibition of histone deacetylases. The present findings demonstrate that decrease of alpha 2-adrenergic receptor expression is a very early event of the HT29 cell differentiation process. They also suggest that SCFAs, which originate from bacterial fermentation of dietary fibers, may play a role in the regulation of the alpha 2-adrenergic receptivity of colonic mucosa in vivo.
Devedjian
J C
JC
Institut National de la Santé et de la Recherche Médical Unité 317, Toulouse, France.
Schaak
S
S
Gamet
L
L
Denis-Pouxviel
C
C
Paris
H
H
D000085:Acetates / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007700:Kinetics; D011422:Propionates / Q000494:pharmacology*; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
C547774:ADRA2C protein, human; D000085:Acetates; D002087:Butyrates; D011422:Propionates; D018341:Receptors, Adrenergic, alpha-2