Premium
A postprandial FGF 19‐ SHP ‐ LSD 1 regulatory axis mediates epigenetic repression of hepatic autophagy
Author(s) -
Byun Sangwon,
Kim YoungChae,
Zhang Yang,
Kong Bo,
Guo Grace,
Sadoshima Junichi,
Ma Jian,
Kemper Byron,
Kemper Jongsook Kim
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695500
Subject(s) - library science , biology , gerontology , medicine , computer science
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 LSD 1 in response to a late fed‐state hormone, FGF 19 ( hFGF 19, mFGF 15). FGF 19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP ‐null mice or LSD 1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF 15‐null mice. Upon FGF 19 treatment or feeding, SHP recruits LSD 1 to CREB ‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC 2, LSD 1‐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 FGF 19‐ SHP ‐ LSD 1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.