Andriamihaja Mireille, Chaumontet Catherine, Tome Daniel, Blachier François
INRA, CNRH-IdF, UMR 914 Nutrition Physiology and Ingestive Behavior, Paris, France.
J Cell Physiol. 2009 Jan;218(1):58-65. doi: 10.1002/jcp.21556.
Butyrate and acetate are bacterial metabolites present in the large intestine lumen. Although butyrate is well known to inhibit the in vitro proliferation of human colon carcinoma cells in a process involving the hyperacetylation of specific nuclear histones, little is known about the possible link between butyrate metabolism and its growth-inhibitory effect. In a previous study (Leschelle et al., 2000, Eur J Biochem 267: 6435-6442), we showed that butyrate accumulates and is metabolized in HT-29 Glc(-/+) cells without increasing oxygen consumption. In the present study, using the same cell line incubated with (14)C-labeled butyrate, we determined that a minor part of (14)C from butyrate was recovered in nuclear histones. Unlike butyrate, acetate exerted no effect on cell growth but was a precursor for overall net histone acetylation. Although butyrate was able to increase the cellular AMP/ADP ratio, it did not affect the ATP cell content or the adenylate charge or the oxidation of endogenous L-glutamine. Butyrate oxidation was found to be markedly sensitive to the presence of other substrates with D-glucose decreasing this oxidation and L-malate stimulating it. Furthermore, in the presence of L-malate, the growth-inhibitory effect of butyrate was significantly weaker than in its absence. From these data, we conclude that the metabolism of butyrate downstream acetyl-CoA synthesis is not involved in the butyrate antiproliferative effect. The suggestion that butyrate metabolism in mitochondria is not used in these cells as a fuel but acts as a regulator of butyrate free concentrations (thus limiting its action upon cellular targets), is discussed.
丁酸和乙酸是存在于大肠肠腔中的细菌代谢产物。尽管众所周知丁酸在一个涉及特定核组蛋白超乙酰化的过程中会抑制人结肠癌细胞的体外增殖，但关于丁酸代谢与其生长抑制作用之间可能的联系却知之甚少。在之前的一项研究中（Leschelle等人，2000年，《欧洲生物化学杂志》267: 6435 - 6442），我们发现丁酸在HT - 29 Glc(-/+）细胞中积累并代谢，且不会增加氧气消耗。在本研究中，使用与（14）C标记的丁酸孵育的同一细胞系，我们确定丁酸中一小部分（14）C在核组蛋白中被回收。与丁酸不同，乙酸对细胞生长没有影响，但却是整体净组蛋白乙酰化的前体。尽管丁酸能够增加细胞内的AMP/ADP比值，但它不影响细胞内ATP含量、腺苷酸电荷或内源性L - 谷氨酰胺的氧化。发现丁酸氧化对其他底物的存在明显敏感，D - 葡萄糖会降低这种氧化，而L - 苹果酸会刺激它。此外，在L - 苹果酸存在的情况下，丁酸的生长抑制作用明显弱于不存在时。根据这些数据，我们得出结论，丁酸在乙酰辅酶A合成下游的代谢不参与丁酸的抗增殖作用。本文讨论了线粒体中丁酸代谢在这些细胞中并非用作燃料而是作为丁酸游离浓度调节剂（从而限制其对细胞靶点的作用）的观点。
