PDF(Pubmed)
Abstract：
Non-alcoholic steatohepatitis (NASH) is an aggressive form of fatty liver disease with hepatic inflammation and fibrosis for which there is currently no drug treatment. This study determined whether an indoline derivative, AN1284, which significantly reduced damage in a model of acute liver disease, can reverse steatosis and fibrosis in mice with pre-existing NASH and explore its mechanism of action. The mouse model of dietary-induced NASH reproduces most of the liver pathology seen in human subjects. This was confirmed by RNA-sequencing analysis. The Western diet, given for 4 months, caused steatosis, inflammation, and liver fibrosis. AN1284 (1 mg or 5 mg/kg/day) was administered for the last 2 months of the diet by micro-osmotic-pumps (mps). Both doses significantly decreased hepatic damage, liver weight, hepatic fat content, triglyceride, serum alanine transaminase, and fibrosis. AN1284 (1 mg/kg/day) given by mps or in the drinking fluid significantly reduced fibrosis produced by carbon tetrachloride injections. In human HUH7 hepatoma cells incubated with palmitic acid, AN1284 (2.1 and 6.3 ng/ml), concentrations compatible with those in the liver of mice treated with AN1284, decreased lipid formation by causing nuclear translocation of the aryl hydrocarbon receptor (AhR). AN1284 downregulated fatty acid synthase (FASN) and sterol regulatory element-binding protein 1c (SREBP-1c) and upregulated Acyl-CoA Oxidase 1 and Cytochrome P450-a1, genes involved in lipid metabolism. In conclusion, chronic treatment with AN1284 (1mg/kg/day) reduced pre-existing steatosis and fibrosis through AhR, which affects several contributors to the development of fatty liver disease. Additional pathways are also influenced by AN1284 treatment.
摘要：
非酒精性脂肪性肝炎(NASH)是脂肪肝疾病的侵袭性形式,其具有肝脏炎症和纤维化,目前没有药物治疗。这项研究确定了二氢吲哚衍生物，AN1284，显着减少急性肝病模型中的损伤，可以逆转已存在NASH的小鼠的脂肪变性和纤维化，并探讨其作用机制。饮食诱导的NASH的小鼠模型再现了在人类受试者中看到的大多数肝脏病理学。这通过RNA测序分析得到证实。西方饮食，给予4个月，引起的脂肪变性,炎症,和肝纤维化。在饮食的最后2个月中，通过微渗透泵（mps）施用AN1284（1mg或5mg/kg/天）。两种剂量都显着减少肝损伤，肝脏重量,肝脏脂肪含量，甘油三酯，血清丙氨酸转氨酶，和纤维化。mps或饮用液中给予AN1284（1mg/kg/天）可显着降低四氯化碳注射液产生的纤维化。在用棕榈酸孵育的人HUH7肝癌细胞中，AN1284（2.1和6.3ng/ml），浓度与用AN1284处理的小鼠肝脏中的浓度相容，通过引起芳香烃受体（AhR）的核易位来减少脂质形成。AN1284下调脂肪酸合成酶（FASN）和固醇调节元件结合蛋白1c（SREBP-1c），上调酰基辅酶A氧化酶1和细胞色素P450-a1，这些基因与脂质代谢有关。总之,AN1284（1mg/kg/天）的慢性治疗通过AhR减少了预先存在的脂肪变性和纤维化，这影响了脂肪肝疾病发展的几个因素。其他途径也受AN1284治疗的影响。
