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  2. Sulfonated albumin from hepatocytes accelerates liver fibrosis in nonalcoholic fatty liver disease through endoplasmic reticulum stress

Sulfonated albumin from hepatocytes accelerates liver fibrosis in nonalcoholic fatty liver disease through endoplasmic reticulum stress

  • Free Radic Biol Med. 2025 Feb 16:228:150-162. doi: 10.1016/j.freeradbiomed.2024.12.055.
Tiantian Liu 1 Minghao Sui 2 Miaomiao Tian 3 Nijin Wu 3 Songbo Zhao 4 Yingchun Wang 4 Yinuo Yang 2 Shujun Ma 5 Deyan Jiao 4 Le Wang 6 Yuemin Feng 7 Yahui Zhang 8 Chengyong Qin 1 Chenxi Liu 9 Jianni Qi 10 Qiang Zhu 11
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 4 Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 5 Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Department of Central Laboratory, 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.
  • 6 Department of Health Care Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 7 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 8 Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 9 Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. Electronic address: liuchenxichency@163.com.
  • 10 Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China; Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. Electronic address: slqijn@126.com.
  • 11 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. Electronic address: zhuqiang@sdu.edu.cn.
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Albumin; Fibrosis; Hepatocyte; Liver disease; Sulfonated albumin.

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