Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression.
Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression.
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DOI：
10.1093/nar/gks066
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发表时间：
2012-06
影响因子：
14.9
通讯作者：
Ramsahoye BH
中科院分区：
文献类型：
--
作者：
Latham T;Mackay L;Sproul D;Karim M;Culley J;Harrison DJ;Hayward L;Langridge-Smith P;Gilbert N;Ramsahoye BH
组蛋白脱乙酰酶(HDAC)活性的化学抑制剂被用作诱导组蛋白超乙酰化和解除基因转录调控的实验工具，但目前尚不清楚HDAC的抑制是否在正常的生理转录调控中发挥作用。使用体外和体内试验，我们表明，当糖酵解超过细胞的有氧代谢能力时积累的乳酸是一种内源性HDAC抑制物，以HDAC依赖的方式解除转录调控。乳酸是一种相对较弱的抑制剂(IC5040 mM)，与已有的抑制剂曲古菌素A和丁酸盐相比，但解除调控的基因与低浓度更有效的抑制剂影响的基因显著重叠。HDAC抑制会导致基因的显著上调和下调，但与HDAC蛋白相关的基因更有可能上调，而不太可能比预期的下调。我们的结果表明，乳酸等内源性短链脂肪酸抑制HDAC的主要作用是促进与HDAC蛋白相关的基因表达。因此，我们认为乳酸可能是一种重要的转录调节因子，将细胞的代谢状态与基因转录联系起来。
Chemical inhibitors of histone deacetylase (HDAC) activity are used as experimental tools to induce histone hyperacetylation and deregulate gene transcription, but it is not known whether the inhibition of HDACs plays any part in the normal physiological regulation of transcription. Using both in vitro and in vivo assays, we show that lactate, which accumulates when glycolysis exceeds the cell’s aerobic metabolic capacity, is an endogenous HDAC inhibitor, deregulating transcription in an HDAC-dependent manner. Lactate is a relatively weak inhibitor (IC50 40 mM) compared to the established inhibitors trichostatin A and butyrate, but the genes deregulated overlap significantly with those affected by low concentrations of the more potent inhibitors. HDAC inhibition causes significant up and downregulation of genes, but genes that are associated with HDAC proteins are more likely to be upregulated and less likely to be downregulated than would be expected. Our results suggest that the primary effect of HDAC inhibition by endogenous short-chain fatty acids like lactate is to promote gene expression at genes associated with HDAC proteins. Therefore, we propose that lactate may be an important transcriptional regulator, linking the metabolic state of the cell to gene transcription.
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影响因子：
2.9
作者：
Schultz, BE;Misialek, S;Wong, L
通讯作者：
Wong, L
影响因子：
11.2
作者：
Thangaraju, Muthusamy;Gopal, Elangovan;Ganapathy, Vadivel
通讯作者：
Ganapathy, Vadivel
影响因子：
64.5
作者：
JEPPESEN, P;TURNER, BM
通讯作者：
TURNER, BM
影响因子：
64.5
作者：
Métivier, R;Penot, G;Gannon, F
通讯作者：
Gannon, F
影响因子：
4.1
作者：
Franck, P;Petitipain, N;Nabet, P
通讯作者：
Nabet, P