The Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
The Wohl Institute for Translational Medicine, Hadassah Medical Center, Jerusalem, Israel.
Front Endocrinol (Lausanne). 2023 Aug 16;14:1226808. doi: 10.3389/fendo.2023.1226808. eCollection 2023.
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.
非酒精性脂肪性肝炎（NASH）是一种侵袭性的脂肪肝疾病，伴有肝炎症和纤维化，目前尚无药物治疗。本研究旨在确定一种吲哚啉衍生物 AN1284 是否可以逆转已有 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 小鼠模型可复制大多数人类患者的肝脏病理学。这一点通过 RNA 测序分析得到了证实。给予西方饮食 4 个月可导致脂肪变性、炎症和肝纤维化。在饮食的最后 2 个月，通过微渗透泵（mps）给予 AN1284（1 毫克或 5 毫克/千克/天）。两种剂量均显著降低肝损伤、肝重、肝脂肪含量、甘油三酯、血清丙氨酸转氨酶和纤维化。通过 mps 或饮用液给予 AN1284（1 毫克/千克/天）可显著减少四氯化碳注射引起的纤维化。在体外用人 HUH7 肝癌细胞孵育棕榈酸，AN1284（2.1 和 6.3 ng/ml），与用 AN1284 治疗的小鼠肝脏中的浓度相匹配，通过核易位芳基烃受体（AhR）导致脂质形成减少。AN1284 下调脂肪酸合酶（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，这些基因参与脂质代谢。总之，慢性给予 AN1284（1 毫克/千克/天）通过 AhR 减少了先前存在的脂肪变性和纤维化，而 AhR 影响了脂肪肝疾病发展的几个贡献者。AN1284 治疗还影响其他途径。
