title: Increased Autophagy Markers Are Associated with Ductular Reaction during the Development of Cirrhosis.
abstract: Autophagy is a regulatory pathway in liver fibrosis. We investigated the roles of autophagy in human cirrhotic livers. Cirrhotic and noncirrhotic liver tissues were obtained from patients with hepatocellular carcinoma, and liver tissues from live donors served as control. Patients with cirrhotic livers had significantly increased levels of various essential autophagy-related genes compared with noncirrhotic livers. In addition, colocalization of autophagy marker microtubule-associated protein 1 light chain 3B (LC3B) with lysosome-associated membrane protein-1, increased levels of lysosome-associated membrane protein-2, and increased maturation of lysosomal cathepsin D were observed in cirrhotic livers. By using dual-immunofluorescence staining, we demonstrated that increased LC3B was located mainly in the cytokeratin 19-labeled ductular reaction (DR) in human cirrhotic livers and in an experimental cirrhosis induced by 2-acetylaminofluorene (AAF) with carbon tetrachloride (CCl4), indicating a conserved response to chronic liver damage. Furthermore, an AAF/CCl4-mediated increase in DR and fibrosis were attenuated after chloroquine treatment, suggesting that the autophagy-lysosome pathway was essential for AAF/CCl4-induced DR-fibrosis. In conclusion, we demonstrated that increased autophagy marker positively correlated with DR during the development of cirrhosis. Therefore, targeting autophagy may hold therapeutic value for liver cirrhosis.
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan.
authors.forename: Tzu-Min
authors.initials: TM
authors.lastname: Hung
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ray-Hwang
authors.initials: RH
authors.lastname: Yuan
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Wei-Pang
authors.initials: WP
authors.lastname: Huang
authors.affiliation: Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan.
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, E-DA Hospital/I-Shou University, Kaohsiung, Taiwan.
authors.forename: Chih-Wen
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hong-Shiee
authors.initials: HS
authors.lastname: Lai
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Surgery, E-DA Hospital, Kaohsiung, Taiwan. Electronic address: pohuang1115@ntu.edu.tw.
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D001343:Autophagy / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged
chemical_list: D015415:Biomarkers; D008869:Microtubule-Associated Proteins; D002251:Carbon Tetrachloride