Maradana Muralidhara Rao, Yekollu Suman Kumar, Zeng Bijun, Ellis Jonathan, Clouston Andrew, Miller Gregory, Talekar Meghna, Bhuyan Zaied Ahmed, Mahadevaiah Sachin, Powell Elizabeth E, Irvine Katharine M, Thomas Ranjeny, O'Sullivan Brendan John
University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
Metabolism. 2018 Jan;78:80-94. doi: 10.1016/j.metabol.2017.09.002. Epub 2017 Sep 20.
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic macrophage inflammation, steatosis and fibrosis. Liposomes injected intravenously passively target hepatic myeloid cells and have potential to deliver immunomodulatory compounds and treat disease. We investigated targeting, delivery, immunomodulation and efficacy of liposomes in mice with diet-induced NASH.
Liposome-encapsulated lipophilic curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol) were injected intravenously into mice with diet-induced NASH. Liver and cell liposome uptake was assessed by in vivo imaging and flow cytometry. Immunomodulation of targeted cells were assessed by RNA transcriptome sequencing. NASH was assessed by histological scoring, serum liver enzymes and fasting glucose/insulin and liver RNA transcriptome sequencing.
Liposomes targeted lipid containing MHC class-II hepatic dendritic cells in mice and humans. Delivery of liposomal curcumin to hepatic dendritic cells shifted their inflammatory profile towards a regulatory phenotype. Delivery of liposomal curcumin or calcitriol to mice with diet-induced NASH led to reduced liver inflammation, fibrosis and fat accumulation, and reduced insulin resistance. RNA transcriptome sequencing of liver from treated mice identified suppression of pathways of immune activation, cell cycle and collagen deposition.
Liposomes are a new strategy to target lipid rich inflammatory dendritic cells and have potential to deliver immunomodulatory compounds to treat NASH.
非酒精性脂肪性肝病（NAFLD）的特征是肝脏巨噬细胞炎症、脂肪变性和纤维化。静脉注射的脂质体可被动靶向肝脏髓样细胞，并具有递送免疫调节化合物和治疗疾病的潜力。我们研究了脂质体在饮食诱导的非酒精性脂肪性肝炎（NASH）小鼠中的靶向性、递送、免疫调节作用及疗效。
将脂质体包裹的亲脂性姜黄素或1,25 - 二羟基维生素D3（骨化三醇）静脉注射到饮食诱导的NASH小鼠体内。通过体内成像和流式细胞术评估肝脏和细胞对脂质体的摄取。通过RNA转录组测序评估靶向细胞的免疫调节作用。通过组织学评分、血清肝酶、空腹血糖/胰岛素以及肝脏RNA转录组测序评估NASH。
脂质体靶向小鼠和人类肝脏中含脂质的MHC II类树突状细胞。将脂质体包裹的姜黄素递送至肝脏树突状细胞可使其炎症表型向调节性表型转变。将脂质体包裹的姜黄素或骨化三醇递送至饮食诱导的NASH小鼠体内可减轻肝脏炎症、纤维化和脂肪堆积，并降低胰岛素抵抗。对治疗后小鼠肝脏进行RNA转录组测序发现免疫激活、细胞周期和胶原蛋白沉积途径受到抑制。
脂质体是靶向富含脂质的炎症性树突状细胞的一种新策略，具有递送免疫调节化合物治疗NASH的潜力。
