| First Author | Mana MD | Year | 2021 |
| Journal | Cell Rep | Volume | 35 |
| Issue | 10 | Pages | 109212 |
| PubMed ID | 34107251 | Mgi Jnum | J:306661 |
| Mgi Id | MGI:6717010 | Doi | 10.1016/j.celrep.2021.109212 |
| Citation | Mana MD, et al. (2021) High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity. Cell Rep 35(10):109212 |
| abstractText | 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, PPARalpha and PPARdelta 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. |
