Nature子刊:禁食激活肝脏自噬和脂质降解,与表观遗传有什么关系?
创作:orchid 审核:mildbreeze 2020年02月19日
  • 禁食诱导的FGF21信号可活化小鼠肝脏中的组蛋白去甲基化酶JMJD3,通过降低抑制基因转录的H3K27me3修饰水平,使自噬基因表达整体上调,增强肝脏自噬和脂质降解;
  • 机制上,FGF21信号活化PKA,使JMJD3在Thr-1044发生磷酸化,促进其进入细胞核并与核受体PPARα互作,进而通过表观遗传机制激活自噬基因转录;
  • 补充FGF21可改善肥胖小鼠的自噬缺陷和脂肪肝,该作用依赖于JMJD3;
  • 脂肪肝患者肝脏中,JMJD3和关键自噬基因的表达明显降低。
主编推荐语
mildbreeze
禁食可以诱导肝脏自噬,促进脂质降解、维持能量平衡,Nature Communications近期发表的一项研究揭示了这一过程的表观遗传机制。该研究表明,禁食诱导的成纤维细胞生长因子21(FGF21)信号,可活化组蛋白去甲基化酶JMJD3,导致组蛋白去甲基化作用介导的自噬基因激活。这些发现或能为治疗脂肪肝提供新的靶点。
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Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase

禁食诱导的FGF21信号通过JMJD3组蛋白去甲基化酶激活肝脏自噬和脂质降解

10.1038/s41467-020-14384-z

2020-02-10, Article

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Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increases its nuclear localization and interaction with the nuclear receptor PPARα to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.

First Authors:
Sangwon Byun

Correspondence Authors:
Jongsook Kim Kemper

All Authors:
Sangwon Byun,Sunmi Seok,Young-Chae Kim,Yang Zhang,Peter Yau,Naoki Iwamori,H Eric Xu,Jian Ma,Byron Kemper,Jongsook Kim Kemper

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