Séminaire de Simon DUCHEIX, PhD - Bari, Italie

Ablation of Stearoyl-CoA Desaturase-1 in the intestinal epithelium drives gut inflammation and tumorigenesis that are rescued by dietary oleate.

ABSTRACT

Stearoyl-CoA desaturase-1 (SCD1) is an enzyme that produces mono-unsaturated fatty acids by introducing double bonds into saturated ones. Its role has been extensively studied in lipogenic organs such as liver and adipose tissue. However, Scd1 expression is also highly regulated in the intestine by dietary challenges, emphasizing its importance in this organ. Given the putative role of fatty acids in cellular proliferation and cancer metabolism, we focused on the role of SCD1 and its product oleic acid in the intestinal epithelium physiology. In order to achieve this goal, we generated mice deficient for Scd1 selectively in the intestinal epithelium, iScd1-/- mice. First, compared to iScd1+/+ mice, ileal mucosa of iScd1-/- mice exhibited lower proportion of monounsaturated fatty acids and a consequent reduction of D9 desaturation ratio between mono-unsaturated (C16:1 n-7 and C18:1 n-9) and saturated (C16:0 and C18:0) fatty acids, respectively. Then, iScd1-/- mice presented gut specific inflammatory markers with activation of ileal proliferation genes that could eventually support dysplastic lesions and cancer. To address this hypothesis, we introduced the ApcMin germline mutation in the iScd1-/- mice and observed that intestinal Scd1 deletion favored tumor progression. Indeed, iScd1-/-ApcMin/+ mice displayed more and larger tumors compared with the iScd1+/+ApcMin/+ mice. We finally proved that dietary supplementation of oleic acid decreased inflammation and strongly reduced cancer burden by at least halving the number and size of tumors. This work suggests that gut specific SCD1 activity is necessary to synthetize oleate and to control intestinal epithelial homeostasis providing protection against inflammation and cancer in vivo.