1. High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.
- Author
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Mana MD, Hussey AM, Tzouanas CN, Imada S, Barrera Millan Y, Bahceci D, Saiz DR, Webb AT, Lewis CA, Carmeliet P, Mihaylova MM, Shalek AK, and Yilmaz ÖH
- Subjects
- Animals, Humans, Mice, Oxidation-Reduction, Carcinogenesis pathology, Diet, High-Fat adverse effects, Fatty Acids metabolism, Intestines pathology, Obesity physiopathology, PPAR alpha metabolism, Stem Cells metabolism
- 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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