@article{a64c193281b442309f828055fa2d8384,
title = "High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity",
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.",
keywords = "Apc, Cpt1a, Ppar, fatty acid oxidation, high-fat diet, intestinal stem cells",
author = "Mana, {Miyeko D.} and Hussey, {Amanda M.} and Tzouanas, {Constantine N.} and Shinya Imada and {Barrera Millan}, Yesenia and Dorukhan Bahceci and Saiz, {Dominic R.} and Webb, {Anna T.} and Lewis, {Caroline A.} and Peter Carmeliet and Mihaylova, {Maria M.} and Shalek, {Alex K.} and Yilmaz, {{\"O}mer H.}",
note = "Funding Information: We thank the Whitehead Institute Metabolite Profiling Core Facility, the Whitehead Institute Flow Cytometry Core, and the Swanson Biotechnology Center at the Koch Institute, which encompasses the Flow Cytometry, Histology, and Genomics & Bioinformatics Core facilities ( NCI P30-CA14051 ). We thank Charlie Whittaker for analysis and helpful discussions regarding RNA sequencing data. We thank the Department of Comparative Medicine for mouse husbandry support. We thank Sven Holder and members of the Hope Babette Tang (1983) Histology Facility for substantial histology support. We thank Heaji Shin and Chia-Wei Cheng for comments on the manuscript, Kerry Kelley for laboratory management, and Liz Galoyan for administrative assistance. M.D.M. received support from the American Cancer Society ( PF-16-202-01-NEC ), an MIT/Ludwig Center for Molecular Oncology postdoctoral fellowship in metastasis/cancer research, and an MIT/Koch Institute quinquennial cancer research fellowship and receives current funding from NIH 1K22CA241083-01 . C.N.T. is supported by a Fannie and John Hertz Foundation fellowship and a National Science Foundation graduate research fellowship ( 1122374 ). P.C. is supported by grants from Methusalem funding (Flemish government), the Fund for Scientific Research-Flanders (FWO-Vlaanderen), and the European Research Council (ERC advanced research grant EU- ERC743074 ). M.M.M. is supported by NIH R00 AG054760 and the American Federation of Aging Research (AFAR). A.K.S. is supported by the Pew-Stewart Scholars Program for Cancer Research . {\"O}.H.Y. is supported by R01CA211184 , R01CA034992 , and U54CA224068 ; a Pew-Stewart Trust scholar award; the Kathy and Curt Marble cancer research award; a Koch Institute-Dana-Farber/Harvard Cancer Center Bridge Project grant; and AFAR . C.N.T., A.K.S., and {\"O}.H.Y. receive support from the MIT Stem Cell Initiative through Fondation MIT . Funding Information: We thank the Whitehead Institute Metabolite Profiling Core Facility, the Whitehead Institute Flow Cytometry Core, and the Swanson Biotechnology Center at the Koch Institute, which encompasses the Flow Cytometry, Histology, and Genomics & Bioinformatics Core facilities (NCI P30-CA14051). We thank Charlie Whittaker for analysis and helpful discussions regarding RNA sequencing data. We thank the Department of Comparative Medicine for mouse husbandry support. We thank Sven Holder and members of the Hope Babette Tang (1983) Histology Facility for substantial histology support. We thank Heaji Shin and Chia-Wei Cheng for comments on the manuscript, Kerry Kelley for laboratory management, and Liz Galoyan for administrative assistance. M.D.M. received support from the American Cancer Society (PF-16-202-01-NEC), an MIT/Ludwig Center for Molecular Oncology postdoctoral fellowship in metastasis/cancer research, and an MIT/Koch Institute quinquennial cancer research fellowship and receives current funding from NIH 1K22CA241083-01. C.N.T. is supported by a Fannie and John Hertz Foundation fellowship and a National Science Foundation graduate research fellowship (1122374). P.C. is supported by grants from Methusalem funding (Flemish government), the Fund for Scientific Research-Flanders (FWO-Vlaanderen), and the European Research Council (ERC advanced research grant EU- ERC743074). M.M.M. is supported by NIH R00 AG054760 and the American Federation of Aging Research (AFAR). A.K.S. is supported by the Pew-Stewart Scholars Program for Cancer Research. ?.H.Y. is supported by R01CA211184, R01CA034992, and U54CA224068; a Pew-Stewart Trust scholar award; the Kathy and Curt Marble cancer research award; a Koch Institute-Dana-Farber/Harvard Cancer Center Bridge Project grant; and AFAR. C.N.T. A.K.S. and ?.H.Y. receive support from the MIT Stem Cell Initiative through Fondation MIT. M.D.M. and A.M.H. designed, conducted, and interpreted the experiments with support from ?.H.Y. C.N.T. and A.K.S. conducted and analyzed scRNA-seq. S.I. D.B. Y.B.M. D.R.S. and A.T.W. provided experimental support. C.A.L. analyzed and interpreted the LC-MS data. P.C. and M.M.M. provided mouse strains. M.M.M. contributed to interpretation of the Ppar experiments. M.D.M. A.M.H. and ?.H.Y. wrote the manuscript, and all authors edited the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = jun,
day = "8",
doi = "10.1016/j.celrep.2021.109212",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}