UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200 Brussels, Belgium.
UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Metabolism and Nutrition Group, Avenue Emmanuel Mounier 73, 1200 Brussels, Belgium; WELBIO (Walloon Excellence in Life sciences and BIOtechnology), WELBIO Department, WEL Research Institute, Avenue Pasteur, 6, 1300 Wavre, Belgium.
J Control Release. 2023 Apr;356:542-553. doi: 10.1016/j.jconrel.2023.03.012. Epub 2023 Mar 15.
Non-alcoholic fatty liver disease (NAFLD) affects approximately 25% of the global adult population and can progress to end-stage liver disease with life-threatening complications; however, no pharmacologic therapy has been approved. Drug delivery systems such as lipid nanocapsules (LNCs) are a very versatile platform, easy to produce, and can induce the secretion of the native glucagon-like peptide 1 (GLP-1) when orally administered. GLP-1 analogs are currently being extensively studied in clinical trials in the context of NAFLD. Our nanosystem provides with increased levels of GLP-1, triggered by the nanocarrier itself, and by the plasmatic absorption of the encapsulated synthetic analog (exenatide). Our goal in this study was to demonstrate a better outcome and a greater impact on the metabolic syndrome and liver disease progression associated with NAFLD with our nanosystem than with the subcutaneous injection of the GLP-1 analog alone. To that end, we studied the effect of chronic administration (one month) of our nanocarriers in two mouse models of early NASH: a genetic model (foz/foz mice fed a high fat diet (HFD)) and a dietary model (C57BL/6J mice fed with a western diet plus fructose (WDF)). Our strategy had a positive impact in promoting the normalization of glucose homeostasis and insulin resistance in both models, mitigating the progression of the disease. In the liver, diverging results were observed between the models, with the foz/foz mice presenting a better outcome. Although a complete resolution of NASH was not achieved in either model, the oral administration of the nanosystem was more efficient at preventing the progression of the disease into more severe states than the subcutaneous injection. We thus confirmed our hypothesis that the oral administration of our formulation has a stronger effect on alleviating the metabolic syndrome associated with NAFLD than the subcutaneous injection of the peptide.
非酒精性脂肪性肝病（NAFLD）影响全球约 25%的成年人口，并可进展为危及生命的并发症的终末期肝病；然而，尚无批准的药物治疗方法。脂质纳米胶囊（LNC）等药物递送系统是一种非常通用的平台，易于生产，并且口服时可以诱导内源性胰高血糖素样肽 1（GLP-1）的分泌。GLP-1 类似物目前正在 NAFLD 的临床试验中广泛研究。我们的纳米系统通过纳米载体本身和封装的合成类似物（艾塞那肽）的血浆吸收来提供增加的 GLP-1 水平。我们在这项研究中的目标是证明我们的纳米系统比单独皮下注射 GLP-1 类似物在代谢综合征和与 NAFLD 相关的肝病进展方面具有更好的效果和更大的影响。为此，我们研究了在两种早期 NASH 小鼠模型中，慢性给予我们的纳米载体（一个月）的效果：一种遗传模型（高脂饮食喂养的 foz/foz 小鼠）和一种饮食模型（western 饮食加果糖喂养的 C57BL/6J 小鼠）。我们的策略对促进两种模型葡萄糖稳态和胰岛素抵抗的正常化产生了积极影响，减轻了疾病的进展。在肝脏中，两种模型之间观察到不同的结果，foz/foz 小鼠的结果更好。尽管在任何一种模型中都没有完全消除 NASH，但与皮下注射相比，口服给予纳米系统更有效地防止疾病向更严重的状态进展。因此，我们证实了我们的假设，即与皮下注射肽相比，口服给予我们的制剂对缓解与 NAFLD 相关的代谢综合征具有更强的作用。
