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Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut
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)...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9434102/ https://www.ncbi.nlm.nih.gov/pubmed/35686465 http://dx.doi.org/10.15252/embj.2021109997 |
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author | Seok, Sunmi Kim, Young‐Chae Zhang, Yang Kong, Bo Guo, Grace Ma, Jian Kemper, Byron Kemper, Jongsook Kim |
author_facet | Seok, Sunmi Kim, Young‐Chae Zhang, Yang Kong, Bo Guo, Grace Ma, Jian Kemper, Byron Kemper, Jongsook Kim |
author_sort | Seok, Sunmi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9434102 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94341022022-09-09 Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut Seok, Sunmi Kim, Young‐Chae Zhang, Yang Kong, Bo Guo, Grace Ma, Jian Kemper, Byron Kemper, Jongsook Kim EMBO J Articles 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. John Wiley and Sons Inc. 2022-06-10 /pmc/articles/PMC9434102/ /pubmed/35686465 http://dx.doi.org/10.15252/embj.2021109997 Text en © 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Articles Seok, Sunmi Kim, Young‐Chae Zhang, Yang Kong, Bo Guo, Grace Ma, Jian Kemper, Byron Kemper, Jongsook Kim Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut |
title | Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut |
title_full | Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut |
title_fullStr | Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut |
title_full_unstemmed | Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut |
title_short | Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut |
title_sort | feeding activates fgf15‐shp‐tfeb‐mediated lipophagy in the gut |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9434102/ https://www.ncbi.nlm.nih.gov/pubmed/35686465 http://dx.doi.org/10.15252/embj.2021109997 |
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