Departments of Medicine, New York Medical College, Valhalla, NY 10595, USA; Department of Drug Science, University of Catania, Catania, Italy.
Departments of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Exp Cell Res. 2019 Jul 15;380(2):180-187. doi: 10.1016/j.yexcr.2019.04.029. Epub 2019 Apr 27.
Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and is considered to be an inflammatory disorder characterized by fatty acid accumulation, oxidative stress, and lipotoxicity. We have previously reported that epoxyeicosatrienoic acid-agonist (EET-A) has multiple beneficial effects on cardiac, renal and adipose tissue function while exhibiting both anti-inflammatory and anti-oxidant activities. We hypothesized that EET-A intervention would play a central role in attenuation of obesity-induced steatosis and hepatic fibrosis that leads to NAFLD.
We studied the effect of EET-A on fatty liver using db/db mice as a model of obesity. Mice were fed a high fat diet (HFD) for 16 weeks and administered EET-A twice weekly for the final 8 weeks.
db/db mice fed HFD significantly increased hepatic lipid accumulation as manifested by increases in NAS scores, hepatic fibrosis, insulin resistance, and inflammation, and decreases in mitochondrial mitofusin proteins (Mfn 1/2) and anti-obesity genes Fibroblast growth factor 21 (FGF21) and Cellular Repressor of E1A-Stimulated Genes 1 (CREG1). EET-A administration reversed the decrease in these genes and reduced liver fibrosis. Knockout of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in EET-A treated mice resulted in a reversal of the beneficial effects of EET-A administration.
EET-A intervention diminishes fatty acid accumulation, fibrosis, and NFALD associated with an increase in HO-1-PGC1α and increased insulin receptor phosphorylation. A pharmacological strategy involving EETs may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NAFLD.
非酒精性脂肪性肝病（NAFLD）与肥胖有关，被认为是一种炎症性疾病，其特征是脂肪酸积累、氧化应激和脂毒性。我们之前报道过，环氧二十碳三烯酸激动剂（EET-A）对心脏、肾脏和脂肪组织功能有多种有益作用，同时具有抗炎和抗氧化作用。我们假设 EET-A 干预将在减轻肥胖引起的脂肪变性和肝纤维化方面发挥核心作用，从而导致 NAFLD。
我们使用 db/db 小鼠作为肥胖模型研究了 EET-A 对脂肪肝的影响。小鼠喂养高脂肪饮食（HFD）16 周，并在最后 8 周每周两次给予 EET-A。
喂食 HFD 的 db/db 小鼠肝脏脂质积累明显增加，表现为 NAS 评分升高、肝纤维化、胰岛素抵抗和炎症增加，以及线粒体融合蛋白（Mfn 1/2）和抗肥胖基因成纤维细胞生长因子 21（FGF21）和细胞 E1A 刺激基因 1 的抑制剂（CREG1）减少。EET-A 给药逆转了这些基因的减少，并减少了肝纤维化。在 EET-A 治疗的小鼠中敲除过氧化物酶体增殖物激活受体γ共激活因子 1-α（PGC-1α）导致 EET-A 给药的有益作用逆转。
EET-A 干预可减少脂肪酸积累、纤维化和与 HO-1-PGC1α 增加和胰岛素受体磷酸化增加相关的 NAFLD。涉及 EET 的药物策略可能为预防纤维化、线粒体功能障碍和 NAFLD 的发展提供一种潜在的治疗方法。
