Luo Xin, Lu Jing-Yi, Shen Zhen-Yang, Ge Qi-Chao, Zhangdi Han-Jing, Wang Jun-Jun, Ye Yan-Ping, Zhang Ling, Luo Ying, Qu Ying, Cai Xiao-Bo, Dong Hui, Lu Lun-Gen
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Continent Pharmaceuticals Co. Ltd., Beijing, China.
FASEB J. 2025 Aug 15;39(15):e70800. doi: 10.1096/fj.202501007R.
Currently, the treatment of Metabolic dysfunction-associated fatty liver disease (MASLD) is limited, and this research aimed to investigate the therapeutic effect and molecular mechanism of Hydronidone (HDD) on MASLD. In our research, High fat and High cholesterol diet (HFHC) as well as Methionine-Choline Deficient diet (MCD) were used to establish the MASLD mouse model. Palmitic Acid (PA)-induced mouse primary hepatocytes (mpHCs) and AML12 cell line were used as cell model. The animal model was treated with three doses of HDD (25/50/100 mg/kg), and the cell model was treated with 0/50/100/200/400 μM HDD respectively. The therapeutic effect of HDD on MASLD models was observed by tissue staining, biochemical tests, qPCR, and Western Blot. Transcriptome sequencing was conducted among the normal control group (NCD group), model group (HFHC group) and medium-dose HDD treatment group (HFHC + 50 mg/kg HDD), through which CD36 was identified as a potential effector gene of HDD. Then, CD36 was overexpressed in the liver by adeno-associated virus on the basis of HFHC+HDD treatment model, and the effects of overexpression of CD36 on HDD treated MASLD mice were observed. The results showed mice in the HDD treatment group had significant improvements in liver steatosis, inflammation, and fibrosis compared with the model group (HFHC/MCD group). Lipid deposition in mpHCs and AML12 cells treated with PA was also significantly reduced after HDD intervention. The results of transcriptome sequencing showed that the expression of genes involved in lipid synthesis, inflammation, and fibrosis were significantly changed in the HDD treatment group. Overexpression of CD36 blocked the therapeutic effect of HDD on MASLD models. HDD could alleviate the disease progression by inhibiting the expression of CD36 in MASLD mice and cell models.
目前，代谢功能障碍相关脂肪性肝病（MASLD）的治疗方法有限，本研究旨在探讨氢化萘醌（HDD）对MASLD的治疗效果及分子机制。在我们的研究中，采用高脂高胆固醇饮食（HFHC）以及蛋氨酸-胆碱缺乏饮食（MCD）建立MASLD小鼠模型。以棕榈酸（PA）诱导的小鼠原代肝细胞（mpHCs）和AML12细胞系作为细胞模型。动物模型分别用三种剂量的HDD（25/50/100 mg/kg）进行治疗，细胞模型分别用0/50/100/200/400 μM的HDD进行治疗。通过组织染色、生化检测、qPCR和蛋白质免疫印迹法观察HDD对MASLD模型的治疗效果。在正常对照组（NCD组）、模型组（HFHC组）和中剂量HDD治疗组（HFHC + 50 mg/kg HDD）之间进行转录组测序，据此确定CD36为HDD的潜在效应基因。然后，在HFHC + HDD治疗模型的基础上，通过腺相关病毒在肝脏中过表达CD36，并观察CD36过表达对HDD治疗的MASLD小鼠的影响。结果显示，与模型组（HFHC/MCD组）相比，HDD治疗组小鼠的肝脂肪变性、炎症和纤维化有显著改善。HDD干预后，PA处理的mpHCs和AML12细胞中的脂质沉积也显著减少。转录组测序结果表明，HDD治疗组中参与脂质合成、炎症和纤维化的基因表达发生了显著变化。CD36的过表达阻断了HDD对MASLD模型的治疗效果。HDD可通过抑制MASLD小鼠和细胞模型中CD36的表达来缓解疾病进展。
