Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, China.
School of Pharmacy, Nanchang University, Nanchang, China.
Elife. 2021 Nov 5;10:e70672. doi: 10.7554/eLife.70672.
Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in multiple biological functions in cell development, differentiation, and transcriptional regulation. deficient mice display the defects of murine glucose metabolism. However, the role of TET1 in metabolic homeostasis keeps unknown. Here, our finding demonstrates that hepatic TET1 physically interacts with silent information regulator T1 (SIRT1) its C-terminal and activates its deacetylase activity, further regulating the acetylation-dependent cellular translocalization of transcriptional factors PGC-1α and FOXO1, resulting in the activation of hepatic gluconeogenic gene expression that includes , , and . Importantly, the hepatic gluconeogenic gene activation program induced by fasting is inhibited in heterozygous mice livers. The adenosine 5'-monophosphate-activated protein kinase (AMPK) activators metformin or AICAR-two compounds that mimic fasting-elevate hepatic gluconeogenic gene expression dependent on in turn activation of the AMPK-TET1-SIRT1 axis. Collectively, our study identifies TET1 as a SIRT1 coactivator and demonstrates that the AMPK-TET1-SIRT1 axis represents a potential mechanism or therapeutic target for glucose metabolism or metabolic diseases.
十号十一号转位甲基胞嘧啶双加氧酶 1（TET1）参与细胞发育、分化和转录调控中的多种生物学功能。TET1 缺陷的小鼠表现出鼠类葡萄糖代谢的缺陷。然而，TET1 在代谢稳态中的作用仍然未知。在这里，我们的发现表明，肝 TET1 与沉默信息调节因子 T1（SIRT1）的 C 端物理相互作用并激活其去乙酰化酶活性，进一步调节转录因子 PGC-1α 和 FOXO1 的乙酰化依赖性细胞易位，导致肝糖异生基因表达的激活，包括 、 和 。重要的是，在 杂合子小鼠肝脏中，禁食诱导的肝糖异生基因激活程序受到抑制。腺苷 5'-单磷酸激活蛋白激酶（AMPK）激活剂二甲双胍或 AICAR-两种模拟禁食的化合物-依赖于 AMPK-TET1-SIRT1 轴的依次激活，从而提高肝糖异生基因表达。总的来说，我们的研究将 TET1 鉴定为 SIRT1 的共激活因子，并表明 AMPK-TET1-SIRT1 轴代表了葡萄糖代谢或代谢疾病的潜在机制或治疗靶点。
