Ginsenoside Rk3 Regulates Nonalcoholic Steatohepatitis by Modulation of Intestinal Flora and the PI3K/AKT Signaling Pathway in C57BL/6 Mice

Abstract

Non-alcoholic steatohepatitis (NASH) has become the most important reason of liver disease around the world and is predisposed to further progression to cirrhosis and hepatocellular carcinoma. Ginsenoside Rk3 has been reported to have a plenty of biological activities, including anti-apoptotic, anti-anemia, and protective effects against acute kidney injury. However, whether ginsenoside Rk3 can improve NASH has not been reported yet. Therefore, the purpose of this study is to investigate the protective effect of ginsenoside Rk3 against NASH and its mechanism of action. C57BL/6 mice were treated with different dosages of ginsenoside Rk3 after being established as a NASH model. Our results showed that Rk3 administration significantly improved liver inflammation, lipid deposition, and fibrosis caused by a high-fat-high-cholesterol (HFHC) diet and CCl4 injection in mice. Notably, ginsenoside Rk3 was discovered significantly to inhibit the PI3K/AKT signaling pathway. Additionally, treatment with ginsenoside Rk3 remarkably amended the abundance of short-chain fatty acids. These changes were associated with beneficial variations to the variety and composition of the intestinal microbiota. In conclusion, ginsenoside Rk3 ameliorates hepatic non-alcoholic lipid inflammation and triggers changes in the beneficial intestinal flora, helping to reveal host–microbe interactions. The outcomes of this study indicate that ginsenoside Rk3 is a promising drug candidate for the treatment of NASH.

Ginsenoside Rk3 Ameliorates Obesity-Induced Colitis by Modulating Lipid Metabolism in C57BL/6 Mice

“…The inhibitory effects of ginsenosides on inflammation have also been reported, but most studies have focused on the gut microbiome and inflammatory signaling pathways. ,, HFD, as an inducing condition, is predominantly altered by fatty acids, so focusing on changes in fatty acid metabolism appears to better represent the role of Rk3 in resisting an HFD. Therefore, PUFAs have garnered significant attention due to their essential role and intriguing characteristics.…”

The gut-liver axis in fatty liver disease: role played by natural products

“…Baicalein, a dietary flavonoid extracted from Scutellaria baicalensis Georgi, can improve lipid levels and hepatic steatosis in choline-deficient diet-induced NAFLD mice through a multi-target and multi-channel mechanism ( Zhang et al, 2022 ). Guo et al (2023) demonstrated that baicalein significantly improved Methionine-Choline Deficient (MCD) diet-induced knot length and restored mucosal barrier integrity by upregulating tight junction protein intestine in mice. In this study, mainly male C57BL/6 mice were used, administered by gavage at 200 mg/kg and 400 mg/kg, respectively, with higher doses showing better therapeutic effects.…”

The role of PI3k/AKT signaling pathway in attenuating liver fibrosis: a comprehensive review

“…Multiple mechanisms control the activity of this pathway, including: Activation of RTKs: Receptor tyrosine kinasеs (RTKs) are transmеmbranе proteins that cross the cell membrane and bind to specific ligands, such as hormones and growth factors. RTKs undergo autophosphorylation in response to ligand binding, leading to the activation of downstream signaling cascades ( 14 ). Ligand binding to RTKs is the main mechanism through which the PI3K/AKT pathway is triggered.…”

“…Several cellular function are regulated by the PI3K/AKT signaling pathway, which is activated by cytokines, various growth factors and other extracellular signals binding to cell surface receptors, initiating a series of intracellular events ( 14 ). The process begins with the activation of PI3K, which phosphorylates PIP2 to generate PIP3 ( 37 , 38 ).…”