Prevention of fatty acid-induced maladaptation in secretin tumor cell-1 enteroendocrine cells by allicin, a transient receptor potential ankyrin 1 agonist

Abstract

Enteroendocrine cells (EECs) in the gastrointestinal tract play a critical role in sensing dietary fat and regulating the secretion of gut hormone. However, chronic high-fat diet (HFD) intake can lead to maladaptive changes in these cells, impairing hormone regulation. Transient receptor potential ankyrin 1 (TRPA1), an ion channel endogenously expressed in EECs, is known to promote gut hormone secretion when activated. Previous studies have shown that gut TRPA1 expression is reduced in HFD-fed mice, but the underlying molecular mechanisms remained unclear. In this study, we used the secretin tumor cell-1 (STC-1) enteroendocrine cell line treated with a fatty acid (FA) mixture (oleic acid: stearic acid in a 2:3 ratio) to mimic chronic HFD exposure in vitro. Our data from label-free proteomics, flow cytometry, and western blotting revealed that FA treatment causes TRPA1 downregulation through AMP-activated protein kinase and Ca2+ signaling pathways. This downregulation was accompanied by altered expression of genes and proteins involved in gut hormone synthesis and secretion. We further investigated the protective effect of allicin, a natural TRPA1 agonist found in garlic. Allicin treatment prevented TRPA1 downregulation both in FA-treated STC-1 cells and in HFD-fed C57BL/6J mice. In conclusion, this study elucidates the AMP-activated protein kinase-dependent mechanisms behind FA-induced TRPA1 downregulation in EECs and highlights how this contributes to gut hormone dysregulation. Importantly, dietary TRPA1 agonists such as allicin can counteract these effects, suggesting potential for development of functional foods (eg, allicin, thiocyanates, cuminaldehyde, cinnamaldehyde) to mitigate HFD-related gut hormone disturbances.