Devedjian J C, Schaak S, Gamet L, Denis-Pouxviel C, Paris H
Institut National de la Santé et de la Recherche Médical Unité 317, Toulouse, France.
Proc Assoc Am Physicians. 1996 Jul;108(4):334-44.
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.
以往对不同物种肠道上皮的研究表明，隐窝未成熟细胞中的α2 - 肾上腺素能受体数量比绒毛成熟细胞中的高几倍，这表明肠细胞分化与这种抑制性受体的表达呈负相关。人结肠黏膜表面 - 隐窝轴上的受体密度与α2C10 mRNA的量相关；然而，这种调节的潜在机制仍然未知。人结肠腺癌细胞系HT29表达α2A - 肾上腺素能受体且能够进行肠细胞分化，是体外研究这个问题的合适模型。在本研究中，我们探讨了结肠腔中正常存在的分化剂短链脂肪酸（SCFAs）对α2 - 肾上腺素能受体表达的影响。将HT29细胞暴露于丁酸盐和丙酸盐而非乙酸盐，导致[3H]RX821002结合位点大幅减少。丁酸盐或丙酸盐诱导的α２ - 肾上腺素能受体数量减少是由于α2C10 mRNA量的减少，并且与碱性磷酸酶活性的增加相关，这反映了更分化表型的出现。两种SCFAs诱导的α2C10 mRNA水平变化是剂量依赖性的、快速且可逆的，并且是由α2C10基因转录速率的降低引起的。最后，曲古抑菌素A模拟了这些作用，表明它们主要是通过抑制组蛋白脱乙酰酶触发的。目前的研究结果表明，α2 - 肾上腺素能受体表达的降低是HT29细胞分化过程中非常早期的事件。它们还表明，源自膳食纤维细菌发酵的SCFAs可能在体内结肠黏膜α2 - 肾上腺素能受体敏感性的调节中发挥作用。
