Isoxanthohumol improves hepatic lipid metabolism via regulating the AMPK/PPARα and PI3K/AKT signaling pathways in hyperlipidemic mice

Abstract Hyperlipidemia presents a significant global healthcare challenge, necessitating innovative therapeutic strategies for more effective outcomes. Recent studies have highlighted the beneficial impact of moderate beer intake on metabolic diseases. The purpose of this research is to explore the possible molecular mechanisms of isoxanthohumol (IXN), the major hop flavonoid in beer, in the treatment of hyperlipidemia. The mice model of acute hyperlipidemia was constructed by intraperitoneal injection of Triton WR‐1339. The therapeutic effect of IXN was assessed by biochemical and histological analyses. Furthermore, comprehensive data mining across various public databases was conducted to identify underlying therapeutic targets of IXN on hyperlipidemia. A protein–protein interaction network was constructed to pinpoint hub targets, and subsequent GO and KEGG enrichment analyses were used to elucidate underlying biological functions. Molecular docking was utilized to validate the binding affinity between hub targets and IXN. Western blotting analysis further verified the protein expression of potential IXN targets. IXN administration significantly improved blood lipid and hepatic lipid levels, alongside increased SOD activity and decreased MDA content in hyperlipidemia mice. Histological analyses, including H&E and Oil Red O staining, showed the improvement of hepatic steatosis with IXN treatment. At the molecular level, IXN significantly increased protein levels of p‐AMPK, PPARα, p‐PI3K, and p‐AKT. IXN activates AMPK/PPARα and PI3K/AKT signaling pathways, leading to reduction in lipid accumulation and oxidative stress, and ultimately ameliorating hyperlipidemia.