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Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α.

肝脏Gadd45β 通过PGC-1α 的DNA去甲基化促进高血糖和葡萄糖耐受不良。

  • 影响因子:9.83
  • DOI:10.1084/jem.20201475
  • 作者列表:"Wu L","Jiao Y","Li Y","Jiang J","Zhao L","Li M","Li B","Yan Z","Chen X","Li X","Lu Y
  • 发表时间:2021-05-03
Abstract

: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.

摘要

尽管由于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 (例如地塞米松) 的处方已经与有害的葡萄糖代谢相关,损害了其长期治疗用途。然而,分子机制仍然知之甚少。在本研究中,通过两种小鼠模型的转录组学和表观基因组学分析,我们鉴定了刺激肝葡萄糖产生 (HGP) 的生长停滞和DNA损伤诱导的 β (Gadd45β) 依赖性途径。功能研究表明,体内或培养肝细胞中Gadd45β 的过表达激活糖异生并增加HGP。相反,肝特异性gadd45β 基因敲除小鼠对高脂肪饮食或类固醇诱导的高血糖具有抗性。具有病理生理学意义的是,肝脏Gadd45β 表达在肥胖和糖尿病患者的几种小鼠模型中上调。在机制上,Gadd45β 与TET1联合促进PGC-1α 启动子的DNA去甲基化,从而刺激PGC-1α 表达以促进糖异生和高血糖。总的来说,这些发现揭示了肝脏葡萄糖代谢中涉及Gadd45β/TET1/DNA去甲基化的表观基因组特征,从而能够鉴定糖尿病的致病因素。

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DOI:10.1007/s11033-021-06299-9
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