Ferulic acid and protocatechuic acid alleviate atherosclerosis by promoting UCP1 expression to inhibit the NLRP3-IL-1β signaling pathway

Dietary phenolic acids can combat metabolic diseases like obesity and non-alcoholic fatty liver by enhancing adipose tissue's thermogenic function. Uncoupling protein 1 (UCP1), a key thermogenic protein, is linked to atherosclerosis (AS) development. Whether dietary phenolic acids inhibit AS by boosting thermogenic function remains unknown. This study aims to identify phenolic acids that can enhance the thermogenic capacity of fat and investigate their roles and mechanisms in alleviating AS. Here, we utilized C3H10T1/2 cells and UCP1-luciferase gene knock-in mice to screen dietary phenolic acids, namely ferulic acid and protocatechuic acid, which could enhance the thermogenic capacity of the organism. Treating ApoE^-/- mice with these phenolic acids reduced aortic plaques and suppressed pro-inflammatory gene expression (<i>il-1β</i>, <i>il-6</i>, <i>tnf-α</i>), while simultaneously promoting thermogenic functionality in interscapular brown adipose tissue and perivascular adipose tissue. Furthermore, applying conditioned media from brown adipose cells whose thermogenic capacity was activated by the phenolic acids to foam cells substantially inhibited the NLRP3-IL-1β inflammatory pathway and suppressed foam cell formation. These studies reveal that ferulic acid and protocatechuic acid can inhibit AS, at least in part, by upregulating UCP1 in adipose tissue, thereby suppressing the NLRP3-IL-1β inflammatory pathway and inhibiting foam cell formation in AS plaques. This validates the potential therapeutic function of phenolic acid compounds selected using UCP1 as a target for treating AS. Our work provides a theoretical basis for the precise utilization of food resources rich in phenolic acid compounds.