Feeding activates FGF15-SHP-TFEB-mediated lipophagy in the gut

EMBO J. 2022 Sep 1;41(17):e109997. doi: 10.15252/embj.2021109997. Epub 2022 Jun 10.

Abstract

Lysosome-mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that, unexpectedly, feeding activates intestinal autophagy/lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the gut hormone, fibroblast growth factor-15/19 (FGF15/19). Furthermore, postprandial intestinal triglycerides (TGs) and apolipoprotein-B48 (ApoB48), the TG-rich chylomicron marker, were elevated in SHP-knockout and FGF15-knockout mice. Genomic analyses of the mouse intestine indicated that SHP partners with the key lysosomal activator, transcription factor-EB (TFEB) to upregulate the transcription of autophagy/lipolysis network genes after feeding. FGF19 treatment activated lipophagy, reducing TG and ApoB48 levels in HT29 intestinal cells, which was dependent on TFEB. Mechanistically, feeding-induced FGF15/19 signaling increased the nuclear localization of TFEB and SHP via PKC beta/zeta-mediated phosphorylation, leading to increased transcription of the TFEB/SHP target lipophagy genes, Ulk1 and Atgl. Collectively, these results demonstrate that paradoxically after feeding, FGF15/19-activated SHP and TFEB activate gut lipophagy, limiting postprandial TGs. As excess postprandial lipids cause dyslipidemia and obesity, the FGF15/19-SHP-TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity-associated metabolic disease.

Keywords: ATGL; FGF19; SHP; TFEB; autophagy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apolipoprotein B-48 / metabolism
  • Autophagy*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / metabolism
  • Eating*
  • Fibroblast Growth Factors* / metabolism
  • Gastrointestinal Tract* / metabolism
  • Lysosomes / metabolism
  • Mice
  • Mice, Knockout
  • Obesity / metabolism
  • Receptors, Cytoplasmic and Nuclear* / metabolism

Substances

  • Apolipoprotein B-48
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Receptors, Cytoplasmic and Nuclear
  • Tcfeb protein, mouse
  • fibroblast growth factor 15, mouse
  • nuclear receptor subfamily 0, group B, member 2
  • Fibroblast Growth Factors