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Article

A postprandial FGF19‐SHP‐LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy

View ORCID ProfileSangwon Byun, Young‐Chae Kim, Yang Zhang, Bo Kong, Grace Guo, Junichi Sadoshima, Jian Ma, Byron Kemper, View ORCID ProfileJongsook Kim Kemper
DOI 10.15252/embj.201695500 | Published online 26.04.2017
The EMBO Journal (2017) e201695500
Sangwon Byun
Department of Molecular and Integrative Physiology, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
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Young‐Chae Kim
Department of Molecular and Integrative Physiology, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
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Yang Zhang
Department of Bioengineering, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
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Bo Kong
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
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Grace Guo
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
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Junichi Sadoshima
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA
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Jian Ma
Department of Bioengineering, University of Illinois at Urbana‐Champaign, Urbana, IL, USAComputational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA
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Byron Kemper
Department of Molecular and Integrative Physiology, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
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Jongsook Kim Kemper
Department of Molecular and Integrative Physiology, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
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Author Affiliations

  1. Sangwon Byun1,
  2. Young‐Chae Kim1,
  3. Yang Zhang2,
  4. Bo Kong3,
  5. Grace Guo3,
  6. Junichi Sadoshima4,
  7. Jian Ma2,5,
  8. Byron Kemper1 and
  9. Jongsook Kim Kemper (jongsook{at}illinois.edu)*,1
  1. 1Department of Molecular and Integrative Physiology, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
  2. 2Department of Bioengineering, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
  3. 3Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
  4. 4Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA
  5. 5Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA
  1. ↵*Corresponding author. Tel: +1 217 333 6317; E‐mail: jongsook{at}illinois.edu
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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

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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.

  • bile acid
  • CREB
  • CRTC2
  • FGF15
  • FXR
  • lipophagy
  • TFEB
  • Received August 15, 2016.
  • Revision received March 31, 2017.
  • Accepted April 4, 2017.
  • © 2017 The Authors
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Volume 37, Issue 8
13 April 2018 | pp -
The EMBO Journal: 37 (8)
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