Short-chain fatty acid metabolism, apoptosis, and Apc-initiated tumorigenesis in the mouse gastrointestinal mucosa.
Short-chain fatty acid metabolism, apoptosis, and Apc-initiated tumorigenesis in the mouse gastrointestinal mucosa.
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发表时间：
1999-12
期刊：
影响因子：
11.2
通讯作者：
L. Augenlicht;G. Anthony;T. Church;W. Edelmann;R. Kucherlapati;K. Yang;M. Lipkin;B. Heerdt
中科院分区：
文献类型：
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作者：
L. Augenlicht;G. Anthony;T. Church;W. Edelmann;R. Kucherlapati;K. Yang;M. Lipkin;B. Heerdt
短链脂肪酸（SCFA）是胃肠道中生长和分化的生理调节剂，并且我们先前已经表明，这些化合物在结肠细胞系中诱导的凋亡依赖于它们在线粒体中通过B-氧化的代谢（B. G. Heerdt等人，生物化学杂志，266：19120-19126，1991; Cancer Res.，54：3288-3293，1994）。由于已报道由遗传性Apc突变引发的肿瘤与胃肠道平坦粘膜中细胞凋亡的减少有关，因此目的是确定SCFA有效代谢的消除是否影响小鼠胃肠道粘膜中的细胞凋亡，以及这种改变是否改变了由遗传性Apc突变引发的肿瘤发生。因此，我们产生的小鼠在Apc基因中具有链终止突变，并且由于编码短链酰基脱氢酶的基因（Scad）的纯合缺失，SCFA代谢为野生型或缺陷型，该酶催化SCFA B氧化的第一步。维持补充麦麸纤维饮食的Scad+/+小鼠的体重比维持AIN 76 A饮食的小鼠显着增加，但这被Scad突变消除，这表明胃肠道中SCFA的吸收和代谢可能是一个重要的能量来源。正如预测的那样，无论是AIN 76 A或麦麸饮食，Scad突变几乎完全消除近端结肠的平坦粘膜中的细胞凋亡，并减少50%的细胞凋亡在远端结肠与同窝出生的野生型Scad相比。该突变还使AIN 76 A喂养小鼠的十二指肠细胞凋亡减少了约50%。这些细胞凋亡的减少对Apc突变引起的肿瘤的发生率、频率或部位特异性没有影响。因此，胃肠道粘膜对SCFA的代谢在调节细胞凋亡中起作用，但胃肠道粘膜中细胞凋亡的普遍减少与遗传性Apc突变引发的胃肠道肿瘤发生无关。
Short-chain fatty acids (SCFAs) are physiological regulators of growth and differentiation in the gastrointestinal tract, and we have previously shown that apoptosis induced in colonic cell lines by these compounds is dependent on their metabolism by B-oxidation in the mitochondria (B. G. Heerdt et al., J. Biol. Chem., 266: 19120-19126, 1991; Cancer Res., 54: 3288-3293, 1994). Because tumors initiated by an inherited Apc mutation have been reported to be linked to decreases in apoptosis in the flat mucosa of the gastrointestinal tract, the aims were to determine whether elimination of efficient metabolism of SCFAs affected apoptosis in the gastrointestinal mucosa of the mouse, and whether this altered tumorigenesis initiated by an inherited Apc mutation. We, therefore, generated mice that have a chain-terminating mutation in the Apc gene and that were either wild-type for SCFA metabolism, or deficient, due to homozygous deletion of the gene (Scad) that encodes the enzyme short-chain acyl dehydrogenase, which catalyzes the first step in SCFA B-oxidation. Scad+/+ mice maintained on a wheat bran-fiber-supplemented diet gained significantly more weight than mice maintained on AIN76A, but this was eliminated by the Scad mutation, demonstrating that uptake and metabolism of SCFAs in the gastrointestinal tract can be a significant energy source. As predicted, on either AIN76A or wheat bran diet, the Scad mutation almost completely eliminated apoptosis in the flat mucosa of the proximal colon and reduced apoptosis by 50% in the distal colon compared with littermates that were wild-type for Scad. The mutation also reduced apoptosis by approximately 50% in the duodenum in AIN76A-fed mice. These reductions in apoptosis had no effect on incidence, frequency, or site specificity of tumors initiated by the Apc mutation. Therefore, the metabolism of SCFAs by the gastrointestinal mucosa plays a role in modulating apoptosis, but a general decrease in apoptosis in the mucosa of the gastrointestinal tract is not linked to gastrointestinal tumorigenesis initiated by an inherited Apc mutation.