High-fat diet activates a PPAR-δ program to enhance intestinal stem cell function

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

“…Next we sought to investigate the in vivo necessity of FAO metabolism in control and HFD ISCs using tamoxifen-inducible and intestine-specific Cpt1a fl/fl ; Vil-CreER; Lgr5-eGFP mice ( Figure 3A ). Consistent with our prior study ( Mihaylova et al, 2018 ), acute deletion of Cpt1a for 4 weeks in control intestines had no effect on OLFM4 + or Lgr5 -EGFP + ISC numbers ( Beyaz et al, 2021 ; Figures 3B – 3E ) or on stem and progenitor cell proliferation, as assessed with a 4-h pulse of bromodeoxyuridine (BrdU + ) ( Figures 3D and S3A ). However, Cpt1a deletion in HFD intestines restored ISC numbers ( Figures 3B and 3D ) and proliferation to control levels ( Figures 3D and S3A ) and blocked the organoid-enhancing effects of a HFD on crypts ( Figure 3F ) and sorted >Lgr5 -EGFP hi ISCs ( Figure 3G ).…”

“…However, given that PPARδ and PPARα play redundant roles in the HFD ISC response, some effects of GW may act through stimulation of PPARα. To address this scenario, we treated WT, Ppard -iKO, Ppara -null, and Ppard/a -iKO organoids with GW for 8 days and performed RNA sequencing to probe the specificity of GW in engaging a PPAR or FAO transcriptional program ( Beyaz et al, 2021 ). Although GW treatment in WT and Ppara -null mice (genotypes with intact PPARδ) led to strong gene set enrichment for signatures related to PPAR signaling pathways and lipid/fatty acid metabolism, Ppard deficiency reduced, but did not entirely eliminate, these signatures as double Ppard/a -deficiency did, nor did Ppard deficiency block the increase in PPAR transcriptional targets ( Figures S1Z – S1BB ).…”

“… (B)–(E) were reprinted from Beyaz et al (2021) . In (A)–(I), mice were fed a purified control diet or HFD.…”

“…(H) Relative abundance of the FAO-mediated metabolites acetylcarnitine and BOHB isolated from freshly harvested crypts of HFD-fed mice and measured by LC-MS. (I) Immunoblot blot of flow-sorted ISCs (Lgr5-EGFP hi ), progenitors (Lgr5-EGFP low ), and epithelial crypt (EpCAM + ) cells from WT and Cpt1a-iKO mice on a control diet or HFD. (B)-(E) were reprinted fromBeyaz et al (2021). In (A)-(I), mice were fed a purified control diet or HFD.…”

Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis

“…Diet contributes to colorectal cancer risk through diverse cancer-cell-intrinsic and cancer-cell-extrinsic mechanisms. Although accumulating evidence demonstrates that pro-obesity or western diets enhance intestinal tumorigenesis in many ways, such as through activation of lipid-sensing PPAR transcription factors (Beyaz et al, , 2021, bile acids (Fu et al, 2019a), alteration of vitamin D signaling (Li et al, 2019), inflammation (Font-Burgada et al, 2016), and the microbiome (Schulz et al, 2014), the role that immune cells play in this process is unclear. Because interactions between the cancer cells and the immune system influence tumor initiation and progression, it is important to understand the crosstalk between tumor-initiating ISCs and immune cells.…”