High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity
Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated recep...
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/135658 |
| _version_ | 1811074394508754944 |
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| author | Mana, Miyeko D Hussey, Amanda M Tzouanas, Constantine N Imada, Shinya Barrera Millan, Yesenia Bahceci, Dorukhan Saiz, Dominic R Webb, Anna T Lewis, Caroline A Carmeliet, Peter Mihaylova, Maria M Shalek, Alex K Yilmaz, Ömer H |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Mana, Miyeko D Hussey, Amanda M Tzouanas, Constantine N Imada, Shinya Barrera Millan, Yesenia Bahceci, Dorukhan Saiz, Dominic R Webb, Anna T Lewis, Caroline A Carmeliet, Peter Mihaylova, Maria M Shalek, Alex K Yilmaz, Ömer H |
| author_sort | Mana, Miyeko D |
| collection | MIT |
| description | Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear. Here we find that, in loss-of-function in vivo models, PPARα and PPARδ contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Pharmacologic and genetic disruption of CPT1A (the rate-controlling enzyme of mitochondrial FAO) blunts the HFD phenotype in ISCs. Furthermore, inhibition of CPT1A dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression. These findings demonstrate that inhibition of a HFD-activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis. |
| first_indexed | 2024-09-23T09:48:46Z |
| format | Article |
| id | mit-1721.1/135658 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:48:46Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1356582024-03-20T19:07:47Z High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity Mana, Miyeko D Hussey, Amanda M Tzouanas, Constantine N Imada, Shinya Barrera Millan, Yesenia Bahceci, Dorukhan Saiz, Dominic R Webb, Anna T Lewis, Caroline A Carmeliet, Peter Mihaylova, Maria M Shalek, Alex K Yilmaz, Ömer H Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Ragon Institute of MGH, MIT and Harvard Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Chemistry Whitehead Institute for Biomedical Research Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear. Here we find that, in loss-of-function in vivo models, PPARα and PPARδ contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Pharmacologic and genetic disruption of CPT1A (the rate-controlling enzyme of mitochondrial FAO) blunts the HFD phenotype in ISCs. Furthermore, inhibition of CPT1A dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression. These findings demonstrate that inhibition of a HFD-activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis. 2021-10-27T20:24:30Z 2021-10-27T20:24:30Z 2021 2021-08-05T14:43:54Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135658 en 10.1016/j.celrep.2021.109212 Cell Reports Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Mana, Miyeko D Hussey, Amanda M Tzouanas, Constantine N Imada, Shinya Barrera Millan, Yesenia Bahceci, Dorukhan Saiz, Dominic R Webb, Anna T Lewis, Caroline A Carmeliet, Peter Mihaylova, Maria M Shalek, Alex K Yilmaz, Ömer H High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity |
| title | High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity |
| title_full | High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity |
| title_fullStr | High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity |
| title_full_unstemmed | High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity |
| title_short | High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity |
| title_sort | high fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity |
| url | https://hdl.handle.net/1721.1/135658 |
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