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

Miyeko D Mana; Amanda M Hussey; Constantine N Tzouanas; Shinya Imada; Yesenia Barrera Millan; Dorukhan Bahceci; Dominic R Saiz; Anna T Webb; Caroline A Lewis; Peter Carmeliet; Maria M Mihaylova; Alex K Shalek; Ömer H Yilmaz

doi:10.1016/j.celrep.2021.109212

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

Cell Rep. 2021 Jun 8;35(10):109212. doi: 10.1016/j.celrep.2021.109212.

Affiliations

¹ Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA. Electronic address: miyeko.mana@asu.edu.
² Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge MA 02139, USA; Program in Health Sciences & Technology, Harvard Medical School, Boston, MA 02115, USA.
⁴ School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.
⁵ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
⁶ Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, and Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, P.R. China; Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.
⁷ Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
⁸ Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: ohyilmaz@mit.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / pathology*
Diet, High-Fat / adverse effects*
Fatty Acids / metabolism*
Humans
Intestines / pathology*
Mice
Obesity / physiopathology*
Oxidation-Reduction
PPAR alpha / metabolism*
Stem Cells / metabolism*

Substances

Fatty Acids
PPAR alpha

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

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