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首页> 外文期刊>Cell metabolism >FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states.
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FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states.

机译：FXR乙酰化通常由p300和SIRT1动态调节，但在代谢性疾病状态下组成性升高。

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The nuclear bile acid receptor FXR is critical for regulation of lipid and glucose metabolism. Here, we report that FXR is a target of SIRT1, a deacetylase that mediates nutritional and hormonal modulation of hepatic metabolism. Lysine 217 of FXR is the major acetylation site targeted by p300 and SIRT1. Acetylation of FXR increases its stability but inhibits heterodimerization with RXRalpha, DNA binding, and transactivation activity. Downregulation of hepatic SIRT1 increased FXR acetylation with deleterious metabolic outcomes. Surprisingly, in mouse models of metabolic disease, FXR interaction with SIRT1 and p300 was dramatically altered, FXR acetylation levels were elevated, and overexpression of SIRT1 or resveratrol treatment reduced acetylated FXR levels. Our data demonstrate that FXR acetylation is normally dynamically regulated by p300 and SIRT1 but is constitutively elevated in metabolic disease states. Small molecules that inhibit FXR acetylation by targeting SIRT1 or p300 may be promising therapeutic agents for metabolic disorders.
机译：核胆汁酸受体FXR对于调节脂质和葡萄糖代谢至关重要。在这里，我们报告FXR是SIRT1的目标，SIRT1是一种脱乙酰基酶，介导肝脏代谢的营养和激素调节。 FXR的赖氨酸217是p300和SIRT1靶向的主要乙酰化位点。 FXR的乙酰化增加了其稳定性，但抑制了具有RXRalpha的异二聚体，DNA结合和反式激活活性。肝脏SIRT1的下调增加了FXR乙酰化，并具有有害的代谢结果。出人意料的是，在代谢性疾病的小鼠模型中，FXR与SIRT1和p300的相互作用被显着改变，FXR乙酰化水平升高，SIRT1或白藜芦醇的过表达降低了乙酰化FXR水平。我们的数据表明，FXR乙酰化通常受p300和SIRT1动态调节，但在代谢疾病状态中组成性升高。通过靶向SIRT1或p300抑制FXR乙酰化的小分子可能是代谢疾病的有前途的治疗剂。

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