Tetrahydroberberrubine improves hyperlipidemia by activating the AMPK/SREBP2/PCSK9/LDL receptor signaling pathway

Hyperlipidemia is a major risk factor for hypertension, coronary heart disease, diabetes and stroke, triggering an intensified research efforts into its prevention and treatment. Tetrahydroberberrubine (THBru) is a derivative of berberine (BBR) that has been shown to have higher bioavailability and lower toxicity compared to its parent compound. However, its impact on hyperlipidemia has not been fully explored. This study was aimed to investigate the effects and potential mechanisms of THBru on hyperlipidemia. Herein, we constructed the hyperlipidemia animal model in C57BL/6J mice through the administration of a 20-week high-fat diet (HFD). The liver damage and lipid metabolism disorders in hyperlipidemic mice were effectively alleviated by THBru (25 or 50 mg/kg) administration. Molecular docking and cellular thermal shift assay (CETSA) have revealed a direct interaction between THBru and the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). THBru was found to downregulate the expression of sterol regulatory element-binding protein 2 (SREBP2) and proprotein convertase subtilisin/kexin type 9 (PCSK9), while upregulate the expression of low-density lipoprotein cholesterol (LDL-C) in the liver of hyperlipidemic mice and lipid metabolism abnormalities cells. The application of AMPK inhibitor in HepG2 cells was able to effectively reverse the regulatory effect of THBru on the AMPK/SREBP2/PCSK9/LDL receptor signaling pathway. In summary, this study for the first time found that THBru is a potential agonist of AMPK, regulate the SREBP2/PCSK9/LDL receptor pathway to improve hyperlipidemia, providing new insights into the prevention and treatment of hyperlipidemia.