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

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.