Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase
Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase
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DOI：
10.1038/s41467-020-14384-z
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发表时间：
2020-02-10
影响因子：
16.6
通讯作者：
Kemper, Jongsook Kim
中科院分区：
文献类型：
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作者：
Byun, Sangwon;Seok, Sunmi;Kemper, Jongsook Kim
自噬对于营养匮乏下的细胞生存和能量稳态至关重要。尽管核事件在自噬调节中的重要性日益凸显，但自噬基因转录的表观遗传控制仍不清楚。在此，我们报告禁食诱导的成纤维细胞生长因子 21 (FGF21) 信号通过 Jumonji-D3 (JMJD3/KDM6B) 组蛋白去甲基酶激活肝自噬和脂质降解。根据 FGF21 信号传导，JMJD3 通过组蛋白 H3K27-me3 去甲基化，表观遗传上调全局自噬网络基因，包括 Tfeb、Atg7、Atgl 和 Fgf21，从而导致自噬介导的脂质降解。从机制上讲，FGF21 信号激活的 PKA 对 JMJD3 Thr-1044 的磷酸化增加了其核定位以及与核受体 PPAR α 的相互作用，从而转录激活自噬。在肥胖小鼠中施用 FGF21 以 JMJD3 依赖性方式改善缺陷性自噬和肝脂肪变性。值得注意的是，在非酒精性脂肪肝患者中，JMJD3、ATG7、LC3 和 ULK1 的肝脏表达显着降低。这些发现表明，FGF21-JMJD3 信号在表观遗传学上将哺乳动物的营养缺乏与肝自噬和脂质降解联系起来。
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 PPAR alpha 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.