Network pharmacology and transcriptomics reveal complanatoside A regulates lipid metabolism in hyperlipidemia and nonalcoholic fatty liver disease via the AMPK pathway.

Nonalcoholic fatty liver disease (NAFLD) and hyperlipidemia belong to the metabolic disorder syndromes of metabolic syndrome. They share a common pathological basis and are often complicated. Complanatoside A (CA), a flavonoid abundant in Astragali complanati semen, helps to prevent NAFLD and hyperlipidemia. However, the exact molecular mechanism is uncertain. Therefore, this study aims to explore the core mechanism. Network pharmacology was used to analyze the preventive mechanism of CA against NAFLD and hyperlipidemia. The efficacy of CA was proven in a high-fat diet-fed mouse model and a steatogenic hepatocyte model. Transcriptomic analysis, Western blot validation, and molecular docking methods were used to explore the common mechanism of CA in preventing NAFLD and hyperlipidemia. Network pharmacology revealed that the AMP-activated protein kinase (AMPK) pathway is a common mechanism leading to NAFLD and hyperlipidemia. It is also a potential pathway by which CA exerts its protective effect, which was confirmed in transcriptomics in vivo. Both in vitro and in vivo experiments showed that CA could inhibit lipid synthesis and promote fatty acid oxidation by activating the AMPK, alleviating lipid accumulation, and lipotoxic liver injury. This was demonstrated by the use of an AMPK inhibitor in vitro. Furthermore, molecular docking results showed that CA could directly interact with AMPK to regulate downstream lipid-related proteins. In conclusion, the AMPK pathway is key in developing NAFLD and hyperlipidemia. CA plays a dual preventive role in NAFLD and hyperlipidemia by activating AMPK to regulate lipid metabolism.