Selective transportation and energy homeostasis regulation of dietary advanced glycation end-products in human intestinal Caco-2 cells

Advanced glycation end-products (AGEs) are a chemically heterogeneous set of modifications widely found in processed foods. Due to uncertain bioavailability, dietary AGEs regulate energy homeostasis through mechanisms that largely remain unclear. In this study, selective transmembrane transport of AGEs with different modification types from glycated beta-casein digest were identified and compared. The results showed that only a few types of free and peptide-bound AGEs can easily cross the Caco-2 monolayers and thus exert their effects. A combination of biochemical assays, mitochondrial analyses, and comparative experiments identified that the effect of AGEs on cellular energy homeostasis comes mainly from their free fractions. Mechanistically, free AGEs arrest the mitochondrial differentiation and mtDNA repair by intervening in the function of thymidine phosphorylase, and interfering with mitochondrial energy production by inhibiting the activation of AMPK-SIRT6 signaling pathway. These results demonstrate mechanisms by which processed foods cause mitochondrial dysfunction and lead to dysfunctional energy homeostasis.

Automated summary

This study identifies the selective transmembrane transport of different modification types of AGEs and their effects on cellular energy homeostasis. The results show that only certain types of free and peptide-bound AGEs can easily cross the cell membrane and exert their effects. Mechanistically, free AGEs interfere with mitochondrial function and energy production through the thymidine phosphorylase and AMPK-SIRT6 signaling pathways.