Effect of saponins from gynostemma pentaphyllum on iron metabolism in apolipoprotein E deficient mice

Gynostemma pentaphyllum (GP) is known as the "elixir of life" in Guizhou Province, China, as it has been widely consumed by the elderly. Numerous studies have shown that gypenosides (GPS) extracted from GP are involved in lipid metabolism. Apolipoprotein E (ApoE) is a polymorphic protein with multiple biological functions, such as regulating lipid transport and iron metabolism. The deficiency of ApoE can lead to disorders in both lipid and iron metabolism. Therefore, ApoE knockout (ApoE^-/-) mice are widely used in the research of disease models related to lipid and iron metabolism. It has been found through research that GPS ameliorates ApoE deficiency-induced dyslipidemia, while our prior research has established ApoE as indispensable for maintaining systemic iron homeostasis. According to the pharmacological effects of GPS, they can regulate lipid metabolism through pathways such as anti-inflammation and oxidative stress. These pathways also play a crucial role in the body's iron metabolism. Thus, this paper hypothesizes that GPS can reverse the abnormal iron metabolism caused by ApoE deficiency. It further explores the impact of GPS on iron metabolism and the underlying mechanism, aiming to provide a theoretical basis for the development of drugs that regulate iron homeostasis.

We randomly divided C57BL/6 mice were randomly divided into blank group (WT), apolipoprotein E knockout group (ApoE KO/ApoE^-/-) and gypenosides group (ApoE^-/- + GPS). The serum iron content, tissue iron content, transferrin receptor 1 (TfR1), ferroportin 1 (Fpn1), divalent metal transporter 1 (DMT1), iron regulatory proteins (IRPs), ferritin light chain (FTL), ferritin heavy chain (FTH), nuclear factor erythroid 2-related factor 2 (NRF2) and hepcidin expression in liver and spleen of the three groups of mice were studied.

The results demonstrate that gypenosides reduce ApoE deficiency-induced iron accumulation by downregulating TfR1 (a cellular iron import protein) and upregulating Fpn1 (an iron export protein). In the spleen of ApoE^-/- mice, this regulation occurs through Nrf2-dependent upregulation of Fpn1 and IRP2-mediated downregulation of TfR1, whereas in the liver, neither Nrf2 nor IRPs play a dominant role in the altered expression of TfR1 and Fpn1 induced by ApoE knockout.

Gypenosides can reduce tissue iron accumulation in the liver and spleen of ApoE-deficient mice, suggesting that, based on its function in regulating lipid metabolism, gypenosides also possess the potential ability to regulate iron metabolism.