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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition
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Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition

机译：短链脂肪酸通过有丝分裂原激活的蛋白激酶激活和组蛋白脱乙酰基酶抑制作用来增强核受体活性

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摘要

In this study, we demonstrate that the pervasive xenobiotic methoxyacetic acid and the commonly prescribed anticonvulsant valproic acid, both short-chain fatty acids (SCFAs), dramatically increase cellular sensitivity to estrogens, progestins, and other nuclear hormone receptor ligands. These compounds do not mimic endogenous hormones but rather act to enhance the transcriptional efficacy of ligand activated nuclear hormone receptors by up to 8-fold in vitro and in vivo. Detailed characterization of their mode of action revealed that these SCFAs function as both activators of p42/p44 mitogen-activated protein kinase and as inhibitors of histone deacetylases at doses that parallel known exposure levels. Our results define a class of compounds that possess a dual mechanism of action and function as hormone sensitizers. These findings prompt an evaluation of previously unrecognized drug-drug interactions in women who are administered exogenous hormones while exposed to certain xenobiotic SCFAs. Furthermore, our study highlights the need to structure future screening programs to identify additional hormone sensitizers.
机译：在这项研究中，我们证明了普遍存在的异源性甲氧乙酸和通常规定的抗惊厥性丙戊酸，均为短链脂肪酸（SCFA），可显着提高细胞对雌激素，孕激素和其他核激素受体配体的敏感性。这些化合物不模仿内源激素，而是在体外和体内将配体激活的核激素受体的转录功效提高多达8倍。它们的作用方式的详细表征表明，这些SCFA既是p42 / p44丝裂原活化蛋白激酶的激活剂，又是组蛋白脱乙酰酶的抑制剂，其剂量与已知的暴露水平相当。我们的结果定义了一类具有双重作用机制并作为激素敏化剂起作用的化合物。这些发现促使人们评估了先前未认识到的在暴露于某些外源性SCFA的同时服用外源激素的女性中的药物相互作用。此外，我们的研究强调需要构建未来的筛查程序，以识别其他激素敏化剂。

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