Luo Jie, Cai Yujie, Jia Chunjian, Zhang Xinfeng, Huang Qifa, Wei Jing, Chen Qi, Chen Tingtao
School of Public Health, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Jiangxi Medical College, Nanchang University, Nanchang 330031, China.
Jiangxi Province Key Laboratory of Bioengineering Drugs, School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang 330031, China.
Int J Biol Macromol. 2025 Mar;294:139446. doi: 10.1016/j.ijbiomac.2024.139446. Epub 2025 Jan 3.
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver diseases worldwide, necessitating urgent novel oral treatments. In this study, β-cell expansion factor A (BefA) was evaluated in a murine NAFLD model induced by high-fat diet (HFD). Our results revealed that BefA significantly reduced body weight (36.58 ± 1.55 g vs. 42.30 ± 1.96 g, p < 0.01), fat mass-to-body weight ratio (0.023 ± 0.019 vs. 0.300 ± 0.019, p < 0.05), liver weight (1.90 ± 0.07 g vs. 2.31 ± 0.21 g, p < 0.05), and liver function parameters (ALT, AST, ALP levels reduced, p < 0.05). Notably, BefA reversed the pathological features of NAFLD, decreasing hepatic steatosis score from 3.67 ± 0.47 to 1.67 ± 0.47 (p < 0.01). Mechanistically, BefA activated the AMPK signaling pathway, resulting in the suppression of lipogenic gene transcription (ACC, FASN, SREBP-1c) and the enhancement of fatty acid oxidation (CPT-1, PPAR-α). However, AMPK inhibitor and broad-spectrum antibiotics significantly attenuated the benefits observed with BefA treatment, increasing body weight, fat-to-body weight ratio, and liver weight (p < 0.05). Similar detrimental effects were also observed in liver function indices and histopathological characteristics. These findings underscore the pivotal role of both gut microbiota modulation and AMPK signaling in BefA's therapeutic efficacy, making it a promising multitargeted approach for NAFLD treatment.
非酒精性脂肪性肝病（NAFLD）是全球慢性肝病的主要原因，因此迫切需要新的口服治疗方法。在本研究中，我们在高脂饮食（HFD）诱导的小鼠NAFLD模型中评估了β细胞扩张因子A（BefA）。我们的结果显示，BefA显著降低了体重（36.58±1.55克对42.30±1.96克，p<0.01）、脂肪量与体重比（0.023±0.019对0.300±0.019，p<0.05）、肝脏重量（1.90±0.07克对2.31±0.21克，p<0.05）以及肝功能参数（ALT、AST、ALP水平降低，p<0.05）。值得注意的是，BefA逆转了NAFLD的病理特征，将肝脏脂肪变性评分从3.67±0.47降至1.67±0.47（p<0.01）。从机制上讲，BefA激活了AMPK信号通路，导致脂肪生成基因转录（ACC、FASN、SREBP-1c）受到抑制，脂肪酸氧化（CPT-1、PPAR-α）增强。然而，AMPK抑制剂和广谱抗生素显著减弱了BefA治疗所观察到的益处，增加了体重、脂肪与体重比以及肝脏重量（p<0.05）。在肝功能指标和组织病理学特征方面也观察到了类似的有害影响。这些发现强调了肠道微生物群调节和AMPK信号在BefA治疗效果中的关键作用，使其成为一种有前途的NAFLD多靶点治疗方法。
