Oh Seung-Hyun, Lee Min-Seong, Lee Byung-Cheol
Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
Int J Mol Sci. 2025 Aug 21;26(16):8079. doi: 10.3390/ijms26168079.
Insulin resistance is a key driver of metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), progressing to non-alcoholic steatohepatitis (NASH). This study investigated the effects of geniposide (GP) on insulin sensitivity and hepatic fibrosis in a high-fat diet (HFD)-induced NASH model. C57BL/6 mice were fed an HFD for five weeks and subsequently divided into normal chow (NC), HFD, HFD with GP 50 mg/kg (GP50), and HFD with GP 100 mg/kg (GP100) groups. The treatments were administered orally for 12 weeks. GP treatment significantly reduced body weight as well as epididymal fat and liver weights, while no differences were observed in food intake. Improvements in glucose and lipid metabolism were observed in oral glucose tolerance tests, homeostatic model assessment of insulin resistance (HOMA-IR), and blood lipid profiles. Histological analyses revealed that GP suppressed adipocyte hypertrophy and hepatic lipid accumulation and hepatic fibrosis. To further elucidate molecular mechanisms of GP, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was conducted in the liver tissue. GP downregulated expression of inflammatory markers, including F4/80, tumor necrosis factor (TNF)-α, and interleukin (IL)-6. GP treatment modulated genes involved in insulin signaling including Janus kinase 2 (JAK2), insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and protein kinase B (AKT1) gene expression levels. This suggests GP suppresses inflammation and mitigates insulin resistance by activating the INSR-IRS2-Akt pathway. Additionally, GP enhanced adenosine monophosphate-activated protein kinase (AMPK) expression, suggesting its potential role in improving glucose and lipid metabolism. In conclusion, GP improves insulin resistance, inflammation, and hepatic fibrosis, highlighting its therapeutic potential for NASH and related metabolic disorders.
胰岛素抵抗是代谢紊乱的关键驱动因素，包括2型糖尿病和非酒精性脂肪性肝病（NAFLD），并进展为非酒精性脂肪性肝炎（NASH）。本研究在高脂饮食（HFD）诱导的NASH模型中研究了栀子苷（GP）对胰岛素敏感性和肝纤维化的影响。将C57BL/6小鼠喂食高脂饮食5周，随后分为正常饲料（NC）、高脂饮食、高脂饮食+50mg/kg GP（GP50）和高脂饮食+100mg/kg GP（GP100）组。治疗口服给药12周。GP治疗显著降低了体重以及附睾脂肪和肝脏重量，而食物摄入量未观察到差异。在口服葡萄糖耐量试验、胰岛素抵抗稳态模型评估（HOMA-IR）和血脂谱中观察到葡萄糖和脂质代谢的改善。组织学分析显示，GP抑制脂肪细胞肥大、肝脏脂质积累和肝纤维化。为了进一步阐明GP的分子机制，在肝组织中进行了定量实时聚合酶链反应（qRT-PCR）分析。GP下调了包括F4/80、肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6在内的炎症标志物的表达。GP治疗调节了参与胰岛素信号传导的基因，包括Janus激酶2（JAK2）、胰岛素受体（INSR）、胰岛素受体底物2（IRS-2）和蛋白激酶B（AKT1）基因表达水平。这表明GP通过激活INSR-IRS2-Akt途径抑制炎症并减轻胰岛素抵抗。此外，GP增强了腺苷单磷酸激活蛋白激酶（AMPK）的表达，表明其在改善葡萄糖和脂质代谢中的潜在作用。总之，GP改善胰岛素抵抗、炎症和肝纤维化，突出了其对NASH和相关代谢紊乱的治疗潜力。
