Ellagic acid modulates UPR-PERK pathway genes, reducing metabolic markers in MAFLD murine model

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a growing global health concern, often progressing from simple steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma (HCC). Obesity and lipotoxicity from high-fat diets drive liver inflammation, a key contributor to MAFLD progression. This inflammation and oxidative stress are intricately linked to endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR) pathway. While new drugs like resmetirom and semaglutide offer treatment, there's a continuous need for complementary therapies targeting distinct mechanisms, such as the UPR pathway.

Researchers investigated the hepatoprotective potential of ellagic acid in a murine model of MAFLD. Mice were fed a high-calorie diet to induce the disease state. The study evaluated ellagic acid's effects by measuring the mRNA expression of specific proteins within the UPR-PERK pathway in both liver and epididymal adipose tissue. Additionally, various metabolic parameters, including glucose, total cholesterol, HDL, VLDL, triglycerides, insulin, and glycated hemoglobin, were assessed. The abstract does not specify the dose, route, frequency, or duration of ellagic acid administration, nor the exact number of animals (n) used in the study.

The high-calorie diet successfully induced MAFLD, activating the UPR pathway in response to cellular stress. This activation was evidenced by increased mRNA expression of key genes: Grp78, Eif2ak3, Eif2α, Ddit3, Atf4, and Nfe2l2 in both liver and epididymal adipose tissue. Treatment with ellagic acid effectively modulated the expression of these UPR-PERK pathway genes, indicating a direct influence on ER stress response. Furthermore, ellagic acid significantly improved several metabolic markers. While specific numerical reductions are not provided in the abstract, the compound was found to reduce levels of glucose, total cholesterol, HDL, VLDL, triglycerides, insulin, and glycated hemoglobin. This broad metabolic improvement supports its role as a hepatoprotective agent. > Ellagic acid modulated the pathway genes and reduced levels of glucose, total cholesterol, HDL and VLDL, triglycerides, insulin, and glycated hemoglobin.