High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity
Name
1-s2.0-S2211124721005623-main.pdf
Description
Published version
Size
3.94 MB
Format
Adobe PDF
Checksum (MD5)
ff0662e40814628a070ad8e8ddc7b711
Author(s)
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
Date Issued
2021
Journal
Cell Reports
Publisher
Elsevier BV
Version
Final published version
Abstract
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.
MIT Department
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
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
10.1016/j.celrep.2021.109212
https://doi.org/10.1016/j.celrep.2021.109212
