Dietary Gallic Acid Alleviates Hypercholesterolemia in High‐Fat‐Diet‐Fed Mice by Modulating Cholesterol and Bile Acid Metabolism

Hypercholesterolemia is a major risk factor for cardiovascular diseases. While gallic acid, a natural phenolic compound, shows hypolipidemic effects, its mechanisms remain elusive. This study investigated gallic acid's modulation of cholesterol and bile acid metabolism in high-fat diet (HFD)-induced hypercholesterolemia. Mice on an HFD were supplemented with gallic acid for 12 weeks. This study systematically examined gallic acid's modulation of cholesterol metabolism (synthesis, uptake, efflux) and enterohepatic bile acid circulation. The results indicated that gallic acid protected mice against diet-induced hypercholesterolemia and hepatic steatosis. Notably, gallic acid intervention favorably altered the dyslipidemic profile by increasing HDL-C while decreasing atherogenic lipids (TG, TC, and LDL-C) in HFD-fed mice. Mechanistically, gallic acid reduced cholesterol accumulation by modulating FXR-mediated liver-gut crosstalk of bile acids, significantly suppressing both ileal and hepatic FXR expression in HFD-fed mice. This inhibition downregulated key FXR target genes (ileal FGF15/SHP/I-BABP/ASBT and hepatic SHP/MAFG), reducing bile acid reabsorption while enhancing hepatic synthesis. Moreover, gallic acid activated Nrf2/HO-1 signaling and promoted antioxidant capacity in HFD-fed mice. Dietary gallic acid alleviates diet-induced hypercholesterolemia and hepatic steatosis, highlighting its potential as a safe and effective dietary supplement for managing hyperlipidemia and preventing metabolic liver disease.