Dataset Information

Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt-FoxO1 Interaction.

ABSTRACT: Rationale: Glucagon is involved in hepatic gluconeogenesis, playing a key role in type 2 diabetes. Ginsenosides are reported to have antidiabetic activities. Ginsenoside Rg1 is a major propanaxatriol-type saponin in ginseng. This study aims to investigate the regulatory effects of Rg1 on glucagon-induced hepatic glucose production. Methods: The effects of Rg1 were investigated in high-fat-diet (HFD)-fed mice and glucagon-challenged C57BL/6J mice. Glucose metabolism was evaluated by oral glucose tolerance test and pyruvate tolerance test. The role of Rg1 on the regulation of Akt-FoxO1 interaction was performed using immunofluorescence, immunoprecipitation, siRNA silencing, pharmacological inhibitor and active-site mutant in primary hepatocytes or HepG2 cells. Results: Abnormally elevated fasting glucagon levels were observed in HFD-fed mice, contributing significantly to increased fasting plasma glucose levels. Inappropriate fasting glucagon secretion inactivated Akt and promoted hepatic glucose production via upregulation of FoxO1 activity. Rg1 preserved glucagon-impaired Akt activation partly by binding to Akt at Ser473 site. Rg1 also promoted Akt binding to FoxO1 and inactivated FoxO1 by phosphorylation. Consequently, Rg1 decreased the hepatic glucose production through a decrease in transcription of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). Both siRNA silencing of Akt and Akt inhibitor triciribine attenuated the effects of Rg1 in response to fasting hormone glucagon. Conclusion: Akt phosphorylation at Ser473 by ginsenoside Rg1 is critical for its gluconeogenesis-lowering effect, suggesting a potential for pharmaceutical intervention in response to fasting hormone glucagon.

SUBMITTER: Liu Q

PROVIDER: S-EPMC5667421 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt-FoxO1 Interaction.

Liu Qun Q Zhang Fei-Ge FG Zhang Wen-Song WS Pan An A Yang Yi-Lin YL Liu Jin-Feng JF Li Ping P Liu Bao-Lin BL Qi Lian-Wen LW

Theranostics 20170920 16

<b>Rationale:</b> Glucagon is involved in hepatic gluconeogenesis, playing a key role in type 2 diabetes. Ginsenosides are reported to have antidiabetic activities. Ginsenoside Rg1 is a major propanaxatriol-type saponin in ginseng. This study aims to investigate the regulatory effects of Rg1 on glucagon-induced hepatic glucose production. <b>Methods:</b> The effects of Rg1 were investigated in high-fat-diet (HFD)-fed mice and glucagon-challenged C57BL/6J mice. Glucose metabolism was evaluated by ...[more]

PMID: 29109794

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Project description:BackgroundDiabetic nephropathy (DN) is one of the most common microvascular complications in diabetes mellitus. Ginsenoside Rg1 (Rg1) is an important active ingredient extracted from Panax ginseng. This study aimed to investigate the role and molecular mechanism of Rg1 in DN model.MethodsThe mesangial cell line HBZY-1 was induced by high glucose (HG; 30 mM D-glucose). HG-induced HBZY-1 cells were treated with Rg1 (2.5, 5, 10 µmol/L). Cell viability was measured by the MTT assay. Apoptosis was detected by flow cytometry. Related proteins were measured by western blot. Reactive oxygen species (ROS) production was measured by dichlorodihydrofluorescein diacetate (DCFH-DA). Inflammatory factors and molecules associated with oxidative stress were detected by enzyme-linked immunoassay (ELISA). DN rats model were treated with 50mg/kg/d Rg1 for 8 weeks, the histopathological changes and the expression of relevant markers were analyzed.ResultsWe found that Rg1 treatment markedly elevated the survival rates of HG-induced HBZY-1 cells and reduced apoptosis induced by HG. Rg1 treatment attenuated the HG-induced inflammatory response by decreasing the high levels of TNF-α, IL-1β, and IL-6. Furthermore, Rg1 treatment alleviated HG-induced oxidative stress by decreasing ROS generation, malondialdehyde (MDA), and lactate dehydrogenase (LDH) accumulation and increasing the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). After Rg1 (50 mg/kg/d) treatment, the severe glomerular thylakoid hyperplasia, glomerular atrophy, tubule dermal cell exfoliation, basement membrane exposure, interstitial edema and inflammatory cell cytoplasmic infiltration were alleviated in DN rats. DN rat model treated with Rg1 (50 mg/kg/d) showed good anti-inflammatory and antioxidant activities. Rg1 treatment also increased the levels of the phosphorylation of PI3K (p-PI3K) and AKT (p-AKT) and promoted the transfer of FOXO3 from the nucleus to the cytoplasm in vitro and in vivo.ConclusionsRg1 exhibited protective effects on DN-induced inflammatory responses and oxidative stress via regulating the PI3K/AKT/FOXO3 pathway in in vitro and in vivo. The results suggest that Rg1 may be a potential therapeutic agent for DN treatment.

Dataset Information

Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt-FoxO1 Interaction.

Publications

Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt-FoxO1 Interaction.

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