Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α.
Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α.
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肝 Gadd45β 通过 PGC-1α 的 DNA 去甲基化促进高血糖和葡萄糖不耐受
DOI：
10.1084/jem.20201475
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发表时间：
2021-05-03
期刊：
影响因子：
--
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Wu L;Jiao Y;Li Y;Jiang J;Zhao L;Li M;Li B;Yan Z;Chen X;Li X;Lu Y
通过转录组学和表观基因组学分析，Wu等人确定了一种糖皮质激素/Gadd 45 β/TET 1依赖性途径，该途径促进PGC-1α基因转录，从而触发肝细胞生成、肝葡萄糖生成和高血糖症。尽管糖皮质激素类似物因其有效的抗炎和免疫抑制特性而被广泛使用，但糖皮质激素类似物的处方（例如，地塞米松）与有害的葡萄糖代谢有关，损害了它们的长期治疗用途。然而，分子机制仍然知之甚少。在本研究中，通过对两种小鼠模型的转录组学和表观基因组学分析，我们确定了一种生长停滞和DNA损伤诱导的β（Gadd 45 β）依赖性途径，该途径刺激肝脏葡萄糖产生（HGP）。功能研究表明，在体内或培养的肝细胞中Gadd 45 β的过表达激活了肝细胞生成并增加了HGP。相比之下，肝脏特异性Gadd 45 β基因敲除小鼠对高脂饮食或类固醇诱导的高血糖症具有抗性。具有病理生理学意义的是，肝脏Gadd 45 β表达在几种肥胖和糖尿病患者的小鼠模型中上调。Gadd 45 β与TET 1共同促进PGC-1α启动子DNA去甲基化，从而刺激PGC-1α表达，促进肿瘤发生和高血糖。总的来说，这些发现揭示了肝脏葡萄糖代谢中涉及Gadd 45 β/TET 1/DNA去甲基化的表观基因组特征，从而能够识别糖尿病的致病因素。
Through transcriptomic and epigenomic analysis, Wu et al. identify a glucocorticoid/Gadd45β/TET1-dependent pathway promoting PGC-1α gene transcription and, thereby, triggering gluconeogenesis, hepatic glucose production, and hyperglycemia. Although widely used for their potent anti-inflammatory and immunosuppressive properties, the prescription of glucocorticoid analogues (e.g., dexamethasone) has been associated with deleterious glucose metabolism, compromising their long-term therapeutic use. However, the molecular mechanism remains poorly understood. In the present study, through transcriptomic and epigenomic analysis of two mouse models, we identified a growth arrest and DNA damage-inducible β (Gadd45β)–dependent pathway that stimulates hepatic glucose production (HGP). Functional studies showed that overexpression of Gadd45β in vivo or in cultured hepatocytes activates gluconeogenesis and increases HGP. In contrast, liver-specific Gadd45β-knockout mice were resistant to high-fat diet– or steroid-induced hyperglycemia. Of pathophysiological significance, hepatic Gadd45β expression is up-regulated in several mouse models of obesity and diabetic patients. Mechanistically, Gadd45β promotes DNA demethylation of PGC-1α promoter in conjunction with TET1, thereby stimulating PGC-1α expression to promote gluconeogenesis and hyperglycemia. Collectively, these findings unveil an epigenomic signature involving Gadd45β/TET1/DNA demethylation in hepatic glucose metabolism, enabling the identification of pathogenic factors in diabetes.
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影响因子：
64.5
作者：
Liu J;Ibi D;Taniguchi K;Lee J;Herrema H;Akosman B;Mucka P;Salazar Hernandez MA;Uyar MF;Park SW;Karin M;Ozcan U
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影响因子：
15.9
作者：
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