Byun Sangwon, Kim Young-Chae, Zhang Yang, Kong Bo, Guo Grace, Sadoshima Junichi, Ma Jian, Kemper Byron, Kemper Jongsook Kim
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
EMBO J. 2017 Jun 14;36(12):1755-1769. doi: 10.15252/embj.201695500. Epub 2017 Apr 26.
Lysosome-mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient-sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed-state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP-null mice or LSD1-depleted mice. In addition, feeding-mediated autophagy inhibition is attenuated in FGF15-null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB-bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1-mediated demethylation of gene-activation histone marks H3K4-me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19-SHP-LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient-rich postprandial conditions.
溶酶体介导的自噬对于营养缺乏时细胞的存活和内环境稳定至关重要，但在进食后会受到抑制。尽管营养感应因子对自噬的转录调控的重要性日益凸显，但表观遗传控制的作用在很大程度上尚未得到探索。在这里，我们表明小异源二聚体伴侣（SHP）通过响应进食后期状态激素FGF19（人FGF19，小鼠FGF15）招募组蛋白去甲基化酶LSD1，介导餐后肝脏自噬的表观遗传抑制。FGF19处理或进食会抑制巨自噬，包括脂噬，但这些作用在SHP基因敲除小鼠或LSD1缺失小鼠中减弱。此外，FGF15基因敲除小鼠中进食介导的自噬抑制作用减弱。在FGF19处理或进食后，SHP将LSD1招募到与CREB结合的自噬基因，包括Tfeb，导致CRTC2解离，LSD1介导基因激活组蛋白标记H3K4-me2/3去甲基化，随后抑制性组蛋白修饰积累。FXR和SHP相互依赖地抑制肝脏自噬，但FXR作用较早，而SHP在进食后作用相对较晚，这有效地维持了餐后对自噬的抑制。这项研究表明，FGF19-SHP-LSD1轴通过在营养丰富的餐后条件下抑制包括脂质在内的细胞成分不必要的自噬分解来维持内环境稳定。
