Portal de Periódicos da CAPES

High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity

2021; Cell Press; Volume: 35; Issue: 10 Linguagem: Inglês

10.1016/j.celrep.2021.109212

2639-1856

Miyeko Mana, Amanda M. Hussey, Constantine N. Tzouanas, Shinya Imada, Yesenia Barrera Millan, Dorukhan Bahceci, Dominic R. Saiz, Anna Webb, Caroline A. Lewis, Peter Carmeliet, Maria M. Mihaylova, Alex K. Shalek, Ömer Yılmaz,

Metabolism, Diabetes, and Cancer

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.