High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity
| Autor: | Constantine N. Tzouanas, Maria M. Mihaylova, Peter Carmeliet, Shinya Imada, Dorukhan Bahceci, Anna T. Webb, Amanda M. Hussey, Ömer H. Yilmaz, Yesenia Barrera Millan, Alex K. Shalek, Miyeko D. Mana, Caroline A. Lewis, Dominic R. Saiz |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Carcinogenesis Peroxisome proliferator-activated receptor medicine.disease_cause COLORECTAL-CANCER Mice 0302 clinical medicine Receptor Beta oxidation fatty acid oxidation chemistry.chemical_classification PPAR-DELTA Ppar Stem Cells Fatty Acids digestive oral and skin physiology food and beverages Peroxisome Phenotype Cell biology Intestines high-fat diet OBESITY lipids (amino acids peptides and proteins) Stem cell Colorectal Neoplasms Oxidation-Reduction Life Sciences & Biomedicine SEQ-WELL RECEPTOR-DELTA Diet High-Fat CELL FUNCTION General Biochemistry Genetics and Molecular Biology Article DIFFERENTIAL EXPRESSION 03 medical and health sciences medicine Animals Humans PPAR alpha Obesity intestinal stem cells Science & Technology nutritional and metabolic diseases Cell Biology Lipid Metabolism GENE Apc Gastrointestinal Microbiome ALPHA 030104 developmental biology chemistry Nuclear receptor Cpt1a 030217 neurology & neurosurgery TUMOR INITIATION |
| Zdroj: | Cell reports Elsevier Mana, M D, Hussey, A M, Tzouanas, C N, Imada, S, Barrera Millan, Y, Bahceci, D, Saiz, D R, Webb, A T, Lewis, C A, Carmeliet, P, Mihaylova, M M, Shalek, A K & Yilmaz, Ö H 2021, ' High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity ', Cell Reports, vol. 35, no. 10, 109212 . https://doi.org/10.1016/j.celrep.2021.109212 CELL REPORTS |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY 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. Graphical abstract In brief Mana et al. demonstrate that a high-fat diet enhances intestinal stemness and tumorigenicity through a PPAR-FAO program. The PPAR family members δ and α redundantly activate a robust FAO program in stem cells where loss or inhibition of CPT1a (the mitochondrial long-chain FAO rate-controlling step) dampens these HFD effects. |
| Databáze: | OpenAIRE |
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