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

  • Biology
  • Genomics
  • Constantine Tzouanas
  • Alex K. Shalek
  • Mana et al.▾
    Mana, M.D., Hussey, A.M., Tzouanas, C.N., Imada, S., Millan, Y.B., Bahceci, D., Saiz, D.R., Webb, A.T., Lewis, C.A., Carmeliet, P., Mihaylova, M.M., Shalek, A.K., Yilmaz, O.H.
  • Cell Reports , Volume 35 , Issue 109212
  • June, 2021
Biology
Genomics
Constantine Tzouanas
Alex K. Shalek

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.

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