Abstract
In individuals with obesity-related non-alcoholic fatty liver disease (NAFLD), endogenous Glucagon-like peptide-1 (GLP-1) secretion is compromised, and supplementation with GLP-1 receptor agonists has shown efficacy in ameliorating NAFLD. However, there is currently a scarcity of research focused on the direct promotion of endogenous GLP-1 secretion from L-cells by plant-derived phenolic acids. Hence, this study reveals that p-Coumaric Acid (p-CA), a widely occurring phenolic acid in the plant, holds potential as a therapeutic approach by stimulating the secretion of GLP-1 to improve glucose-lipid metabolism alterations and alleviate NAFLD symptoms. In diet-induced obese (DIO) mouse models, administration of high doses of p-CA led to a significant elevation in serum GLP-1 levels, as well as improvements in body weight gain, glucose level, insufficient insulin secretion, and biochemical abnormalities associated with NAFLD in mice fed with a high-fat diet. Moreover, the number of lipid droplets in the liver tissue of p-CA-treated mice was notably reduced, suggesting its effectiveness in mitigating liver fat accumulation and ameliorating NAFLD severity. Experimental evidence suggests that p-CA exerts its effects by influencing the transcriptional regulation of Glucose-regulated protein 78 kDa (GRP78) through interaction with Nucleophosmin 1 (NPM1), thereby downregulating GRP78 expression. This decrease in GRP78 expression subsequently leads to an increase in intracellular Calcium ions (Ca2+) concentration, which promotes the production and exocytosis of GLP-1-containing vesicles in L cells, consequently enhancing GLP-1 secretion. This research demonstrates the mechanistic role and therapeutic effects of p-CA in regulating GLP-1 secretion and its implications for improving NAFLD, underscoring the pharmacological significance of this natural compound as a dietary supplement.
Published Version
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