Unlocking the potential of nutrient-dependent regulation of Wnt signaling pathway and lipid metabolism in intestinal cells

Abstract

Aging diminishes the body's ability to regenerate tissues, a decline particularly significant in the gastrointestinal tract where it increases susceptibility to damage and chronic diseases like colorectal cancer. Effective tissue regeneration is crucial for maintaining intestinal homeostasis and preventing disease, yet the underlying regulatory mechanisms, especially how they are influenced by nutrient availability, remain only partly understood. The Wnt signaling pathway plays a key role in driving cell proliferation and is essential for stem cell function. This study explores the role of Stearoyl-CoA desaturase (Scd) enzymes, which may mediate the Wnt signaling. Understanding these interactions may offer new therapeutic avenues for age-related regenerative decline and colorectal cancer. To examine how the inhibition of Scd enzymes affects stem cell function and proliferation, both pharmacological inhibition in vitro and in vivo approaches were utilized, including studies on intestinal crypts, organoids, and fibroblast cell lines. Nutrient availability and dietary content were also varied to assess the role of dietary modulation on the regulation of Scds and Wnt signaling. The key findings of this study indicate that pharmacological inhibition of Scds in vitro in fibroblast cells reduces the proliferation and function of intestinal stem cells, as evidenced by a decrease in organoid formation from the intestinal crypt cells. Additionally, deletion of Scd genes in mice resulted in decreased β-catenin activation, which impaired Wnt signaling. This emphasizes the potential role of Scd enzymes in the modulation of the Wnt signaling pathway. Specifically, the inhibition of Scd specifically reduced the activation of the Wnt-2b and Wnt-3a ligands, indicating that Scd has a selective effect on these Wnt ligands. Dietary modulation further revealed that a monounsaturated fatty acid-rich diet enhanced Wnt signaling in vivo, while nutrient deprivation suppressed Wnt signaling, highlighting a dietary link to regulation of Wnt activity.