Lee Pei-Chang, Yang Ling-Yu, Wang Ying-Wen, Huang Shiang-Fen, Lee Kuei-Chuan, Hsieh Yun-Cheng, Yang Ying-Ying, Hsieh Shie-Liang, Hou Ming-Chih, Lin Han-Chieh, Lee Fa-Yuah, Lee Shou-Dong
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
Hepatol Res. 2017 Nov;47(12):1260-1271. doi: 10.1111/hepr.12863. Epub 2017 Mar 24.
Treatment of non-alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non-decoy effects of DcR3 on diet-induced NASH mice.
Methionine- and choline-deficient (MCD) diet feeding for 9 weeks was applied to induce NASH in BALB/c mice. Decoy receptor 3 heterozygous transgenesis or pharmacological pretreatment with DcR3a for 1 month were designed as interventions. Intrahepatic inflammatory status as well as macrophage polarization, oxidative stress, and steatosis as well as lipogenic gene expression and fibrotic status were analyzed. Additionally, acute effects of DcR3a on HepG2 cells, Hep3B cells, and primary mouse hepatocytes in various MCD medium-stimulated changes were also evaluated.
Both DcR3 genetic and pharmacologic supplement significantly reduced MCD diet-induced hepatic M1 polarization. In addition, DcR3 supplement attenuated MCD diet-increased hepatic inflammation, oxidative stress, adipocytokine imbalance, steatosis, and fibrogenesis. Moreover, acute DcR3a incubation in HepG2 cells, Hep3B cells, and mouse hepatocytes could normalize the expression of genes related to lipid oxidation along with inflammation and oxidative stress.
The ability of DcR3 to attenuate hepatic steatosis and inflammation through its non-decoy effects of immune modulation and oxidative stress attenuation makes it a potential treatment for NASH.
由于缺乏经证实的治疗方法及其综合机制，非酒精性脂肪性肝炎（NASH）的治疗颇具难度。在NASH动物模型中，肝脏炎症和氧化应激上调，导致巨噬细胞M1极化以及脂肪细胞因子失衡，所有这些都会加速NASH的进展。作为肿瘤坏死因子受体超家族的一员，诱饵受体3（DcR3）不仅能中和死亡配体，还能进行免疫调节。在本研究中，我们旨在探讨DcR3对饮食诱导的NASH小鼠可能存在的非诱饵效应。
采用蛋氨酸和胆碱缺乏（MCD）饮食喂养9周，诱导BALB/c小鼠发生NASH。将诱饵受体3杂合转基因或用DcR3a进行1个月的药物预处理设计为干预措施。分析肝内炎症状态以及巨噬细胞极化、氧化应激、脂肪变性以及脂肪生成基因表达和纤维化状态。此外，还评估了DcR3a对各种MCD培养基刺激下HepG2细胞、Hep3B细胞和原代小鼠肝细胞的急性影响。
DcR3基因和药物补充均显著降低了MCD饮食诱导的肝脏M1极化。此外，DcR3补充减轻了MCD饮食引起的肝脏炎症、氧化应激、脂肪细胞因子失衡、脂肪变性和纤维化。此外，在HepG2细胞、Hep3B细胞和小鼠肝细胞中急性孵育DcR3a可使与脂质氧化以及炎症和氧化应激相关的基因表达正常化。
DcR3通过其免疫调节和氧化应激减轻的非诱饵效应减轻肝脏脂肪变性和炎症的能力，使其成为NASH的潜在治疗方法。
