Liu Tiantian, Sui Minghao, Tian Miaomiao, Wu Nijin, Zhao Songbo, Wang Yingchun, Yang Yinuo, Ma Shujun, Jiao Deyan, Wang Le, Feng Yuemin, Zhang Yahui, Qin Chengyong, Liu Chenxi, Qi Jianni, Zhu Qiang
Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China; Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China; Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
Free Radic Biol Med. 2025 Feb 16;228:150-162. doi: 10.1016/j.freeradbiomed.2024.12.055. Epub 2024 Dec 30.
Posttranslational modifications (PTM) of albumin occur in liver diseases; however, little is known about the source and function of sulfonated albumin, a significant modification of albumin occurring in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the mechanism underlying sulfonated albumin production and its role in the progression of NAFLD-related liver fibrosis.
Serum samples from healthy controls and patients with NAFLD were used to measure the proportion of sulfonated albumin. Mice models with NAFLD fed with high-fat diet (HFD) and methionine choline-deficient diet (MCD) were constructed. RNA sequencing, KEGG analysis, and GSEA were used to explore the mechanism of sulfonated albumin production and its mechanism of activating hepatic stellate cells (HSCs) and promoting the progression of liver fibrosis in NAFLD.
Sulfonated albumin levels increased significantly in both human and mouse NAFLD serum samples. In vivo studies in mice have shown that the intraperitoneal injection of sulfonated albumin promotes inflammation, hepatic steatosis, and liver fibrosis in NAFLD. In addition, autophagy has been verified as a key mechanism in the regulation of sulfonated albumin production. We also demonstrated that reactive oxygen species (ROS) production depends on the accumulation of damaged mitochondria and affects the production of sulfonated albumin under the regulation of autophagy. Hepatocyte-derived sulfonated albumin activates HSCs through the GAL3 receptor, thereby activating the endoplasmic reticulum (ER) stress pathway and promoting profibrotic activation of HSCs.
Our study demonstrated that sulfonated albumin activated HSCs through GAL3, thereby accelerating NAFLD-related liver fibrosis. Serum sulfonated albumin may be a potential diagnostic marker for liver fibrosis and an important target for the treatment of NAFLD-related liver fibrosis.
白蛋白的翻译后修饰（PTM）在肝脏疾病中会发生；然而，关于磺化白蛋白的来源和功能知之甚少，磺化白蛋白是白蛋白在非酒精性脂肪性肝病（NAFLD）中发生的一种重要修饰。我们旨在研究磺化白蛋白产生的机制及其在NAFLD相关肝纤维化进展中的作用。
使用来自健康对照者和NAFLD患者的血清样本测量磺化白蛋白的比例。构建喂食高脂饮食（HFD）和蛋氨酸胆碱缺乏饮食（MCD）的NAFLD小鼠模型。采用RNA测序、KEGG分析和基因集富集分析（GSEA）来探索磺化白蛋白产生的机制及其激活肝星状细胞（HSCs）和促进NAFLD肝纤维化进展的机制。
人和小鼠NAFLD血清样本中的磺化白蛋白水平均显著升高。小鼠体内研究表明，腹腔注射磺化白蛋白会促进NAFLD中的炎症、肝脂肪变性和肝纤维化。此外，自噬已被证实是调节磺化白蛋白产生的关键机制。我们还证明，活性氧（ROS）的产生取决于受损线粒体的积累，并在自噬的调节下影响磺化白蛋白的产生。肝细胞衍生的磺化白蛋白通过GAL3受体激活HSCs，从而激活内质网（ER）应激途径并促进HSCs的促纤维化激活。
我们的研究表明，磺化白蛋白通过GAL3激活HSCs，从而加速NAFLD相关的肝纤维化。血清磺化白蛋白可能是肝纤维化的潜在诊断标志物，也是治疗NAFLD相关肝纤维化的重要靶点。
