Ellagic Acid Attenuates MASLD by Reducing Hepatic Lipogenesis and Fibrosis in ApoE ^–/– Mice Fed a Cholesterol- and Cholate-Rich Paigen Diet

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition with a rising global incidence, closely linked to metabolic risk factors such as dyslipidemia. Apolipoprotein E-deficient (ApoE^-/^-) mice fed a Paigen diet are an established model for MASLD and atherosclerosis research. This study investigated the effects of ellagic acid (EA) on MASLD progression in ApoE^-/^- mice fed a Paigen diet. Wild-type (WT) and ApoE^-/^- mice were fed a Paigen diet for 10 weeks to induce metabolic dysregulation. ApoE^-/^- mice were concurrently administered either EA (10 mg/kg/day orally) or no treatment. After 10 weeks, ApoE^-/^- mice exhibited significant hepatic lipid accumulation, confirmed by increased Oil Red O staining. EA treatment significantly reduced hepatic lipid accumulation and lipid peroxidation. Furthermore, EA administration decreased hepatic expression of lipogenic proteins, including sterol regulatory element-binding protein 1, fatty acid synthase, and CCAAT/enhancer-binding protein alpha. The hepatic fibrogenic marker, α-smooth muscle actin (α-SMA), was significantly elevated in ApoE^-/^- mice compared with WT, and was significantly reduced by EA. In addition, transforming growth factor-β (TGF-β) protein levels and downstream SMAD signaling components, including phosphorylated SMAD2 and total SMAD2, SMAD3, and SMAD4, were significantly attenuated by EA treatment. In conclusion, EA effectively ameliorated MASLD and hypercholesterolemia in ApoE^-/^- mice fed a Paigen diet. The beneficial effects of EA may be mediated through downregulating lipogenic pathways and suppressing TGF-β/SMAD signaling.