title: Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Infectious Diseases, the First Affiliated Teaching Hospital, School of Medicine, Xi'an JiaoTong University, Xi'an, Shaanxi Province, China.|Institution of Hepatology, the First Affiliated Hospital of Xi'an JiaoTong University, School of Medicine, Xi'an, Shaanxi Province, China.
authors.forename: YingLi
authors.initials: Y
authors.lastname: He
authors.affiliation: The School of Pharmaceutical Engineering, Guizhou Institute of Technology, Guiyang, 550003, Guizhou, China. zhujinqiu@git.edu.cn.
authors.forename: JinQiu
authors.initials: J
authors.lastname: Zhu
authors.affiliation: The School of Pharmaceutical Engineering, Guizhou Institute of Technology, Guiyang, 550003, Guizhou, China.
authors.forename: YaQi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Xi'an Health School, Xi'an, Shaanxi Province, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Gao
authors.affiliation: 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.|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.|Department of Infectious Diseases, the First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, 710061, Shaanxi Province, China. zhaoyingren@mail.xjtu.edu.cn.
authors.forename: YingRen
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D000951:Antigens, Neoplasm / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006526:Hepatitis C / Q000150:complications / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000494:pharmacology; D061251:Primary Cell Culture; D051381:Rats
chemical_list: D000199:Actins; D000951:Antigens, Neoplasm; D024042:Collagen Type I; D017127:Glycation End Products, Advanced; D020928:Mitogen-Activated Protein Kinases; C498862:Acta2 protein, rat; C498978:MOK protein, human
keywords: Advanced glycation end products; Autophagy; Fibrosis; Hepatic stellate cells; Hepatitis C; Insulin resistance