Abstract
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.
Synopsis
Nutrient state affects autophagy via distinct pathways. The fed‐state hormone FGF19 triggers SHP‐dependent recruitment of LSD1 to CREB‐bound autophagy genes, leading to repressive histone modifications, thus revealing an epigenetic inhibition of hepatic autophagy under nutrient‐rich conditions.
SHP represses hepatic autophagy, including autophagy‐mediated lipid catabolism, “lipophagy”, in response to a late fed‐state hormone, FGF19 (human FGF19, mouse FGF15).
Feeding‐mediated inhibition of hepatic autophagy is blunted in mice lacking SHP or FGF15.
SHP mediates postprandial epigenetic repression of CREB‐bound autophagy genes by recruiting LSD1 histone demethylase.
Feeding‐sensing nuclear receptors FXR and SHP inhibit hepatic autophagy in a mutually dependent manner.
- Received August 15, 2016.
- Revision received March 31, 2017.
- Accepted April 4, 2017.
- © 2017 The Authors
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