YingLi He1,2, JinQiu Zhu3, YaQi Huang4, Heng Gao5, YingRen Zhao6,7,8. 1. Department of Infectious Diseases, the First Affiliated Teaching Hospital, School of Medicine, Xi'an JiaoTong University, Xi'an, Shaanxi Province, China. 2. Institution of Hepatology, the First Affiliated Hospital of Xi'an JiaoTong University, School of Medicine, Xi'an, Shaanxi Province, China. 3. The School of Pharmaceutical Engineering, Guizhou Institute of Technology, Guiyang, 550003, Guizhou, China. zhujinqiu@git.edu.cn. 4. The School of Pharmaceutical Engineering, Guizhou Institute of Technology, Guiyang, 550003, Guizhou, China. 5. Xi'an Health School, Xi'an, Shaanxi Province, China. 6. Department of Infectious Diseases, the First Affiliated Teaching Hospital, School of Medicine, Xi'an JiaoTong University, Xi'an, Shaanxi Province, China. zhaoyingren@mail.xjtu.edu.cn. 7. Institution of Hepatology, the First Affiliated Hospital of Xi'an JiaoTong University, School of Medicine, Xi'an, Shaanxi Province, China. zhaoyingren@mail.xjtu.edu.cn. 8. Department of Infectious Diseases, the First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, 710061, Shaanxi Province, China. zhaoyingren@mail.xjtu.edu.cn.
Abstract
AIMS: Advanced glycation end products (AGEs) have been implicated in pulmonary and renal fibrosis. Herein, we investigated whether AGEs are associated with liver fibrosis and examined the underlying mechanism by focusing on hepatic stellate cell (HSC) activation and autophagy induction. METHODS: Liver fibrosis was assessed by transient elastography (FibroScan). Serum AGE levels were determined by ELISA. Rat primary HSCs and HSC-T6 were treated with BSA-AGEs, cell proliferation was examined by WST-1 assay, and cell activation was evaluated by qPCR for transcripts of α-SMA and collagen type Iα1 and by Western blotting. Autophagy was measured by detection of LC3-II lipidation, p62 degradation, and puncta GFP-LC3 formation. Receptor of AGE (RAGE)-blocking antibodies and soluble RAGE were employed to inhibit AGE-RAGE signaling. RESULTS: First, elevated AGE levels were observed in CHC patients than patients with chronic hepatitis B, especially in those with insulin resistance. Second, compared to controls, AGE-treated rat primary HSCs displayed an enhanced cell proliferation (1.39-fold), increased transcripts of α-SMA (2.40-fold) and proCOL1A1 (1.76-fold), and a higher level of α-SMA protein (1.85-fold). Moreover, AGE-induced HSC activation improved autophagy flux, as evidenced by significantly more LC3-II lipidation, p62 degradation, as well as GFP-LC3 puncta formations. In addition, our results showed that AGE-induced HSC autophagy and HSC activation could be reduced by RAGEs. CONCLUSION: AGEs were found to induce autophagy and activation of HSCs, which subsequently contributes to the fibrosis in CHC patients. Blocking AGE-RAGE signaling may be a promising way to alleviate fibrosis.
AIMS: Advanced glycation end products (AGEs) have been implicated in pulmonary and renal fibrosis. Herein, we investigated whether AGEs are associated with liver fibrosis and examined the underlying mechanism by focusing on hepatic stellate cell (HSC) activation and autophagy induction. METHODS:Liver fibrosis was assessed by transient elastography (FibroScan). Serum AGE levels were determined by ELISA. Rat primary HSCs and HSC-T6 were treated with BSA-AGEs, cell proliferation was examined by WST-1 assay, and cell activation was evaluated by qPCR for transcripts of α-SMA and collagen type Iα1 and by Western blotting. Autophagy was measured by detection of LC3-II lipidation, p62 degradation, and puncta GFP-LC3 formation. Receptor of AGE (RAGE)-blocking antibodies and soluble RAGE were employed to inhibit AGE-RAGE signaling. RESULTS: First, elevated AGE levels were observed in CHCpatients than patients with chronic hepatitis B, especially in those with insulin resistance. Second, compared to controls, AGE-treated rat primary HSCs displayed an enhanced cell proliferation (1.39-fold), increased transcripts of α-SMA (2.40-fold) and proCOL1A1 (1.76-fold), and a higher level of α-SMA protein (1.85-fold). Moreover, AGE-induced HSC activation improved autophagy flux, as evidenced by significantly more LC3-II lipidation, p62 degradation, as well as GFP-LC3 puncta formations. In addition, our results showed that AGE-induced HSC autophagy and HSC activation could be reduced by RAGEs. CONCLUSION: AGEs were found to induce autophagy and activation of HSCs, which subsequently contributes to the fibrosis in CHCpatients. Blocking AGE-RAGE signaling may be a promising way to alleviate fibrosis.
Authors: Ahmed Abdel-Razik; Nasser Mousa; Sahar Zakaria; Mostafa Abdelsalam; Mohamed Eissa; Mohammed I Abd El-Ghany; Ahmad S Hasan; Rania Elhelaly; Rasha Elzehery; Niveen El-Wakeel; Waleed Eldars Journal: Front Med (Lausanne) Date: 2020-10-26