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.

Increased Autophagy-Related 5 Gene Expression Is Associated with Collagen Expression in the Airways of Refractory Asthmatics

“…It has been postulated that autophagy serves as a cell survival mechanism to remove triggers that are threatening cell survival, yet when such threats become overwhelming, cell death processes such as apoptosis and necrosis take over (18, 19). Dysregulation of autophagy has been linked to fibrosis in a number of fibrotic diseases, including cirrhosis (20), idiopathic pulmonary fibrosis (21), and renal fibrosis (22). The upregulation of autophagy during activation of fibrogenic cells, such as hepatic stellate cells from mice as well as hepatitis B-, hepatitis C-virus-infected human liver, and human fibroblasts from idiopathic pulmonary fibrosis, suggests that autophagy is a central pathway in fibrosis (23, 24).…”

p62 Promotes Amino Acid Sensitivity of mTOR Pathway and Hepatic Differentiation in Adult Liver Stem/Progenitor Cells

“…For example, a recent study demonstrated that, in the cirrhotic liver, expression of autophagy‐related genes such as LC3B was increased compared with in the non‐cirrhotic liver. Furthermore, localization of LC3B was consistent with the cholangiocyte and liver progenitor marker, CK19, in humans and rodents (Hung et al, ). This study also revealed that inhibition of autophagy attenuated the ductular reaction and fibrosis in the liver in a drug‐induced cirrhotic model.…”

Complex Cell Type-Specific Roles of Autophagy in Liver Fibrosis and Cirrhosis

“…Autophagy has not been measured directly in the liver of patients with cirrhosis; accordingly, we performed an immunodetection assay of LC3B puncta in fresh-frozen tissues. A dual-immunofluorescence analysis of cirrhotic livers demonstrated the localization of LC3B to CK19-positive RDCs [36], providing the first in vivo evidence, to our knowledge, for the regulation of autophagy in fibrogenic cells other than HSCs. A progressive increase in LC3B and CK19 expression was observed in diseased human liver as the severity of fibrosis increased from the F1 stage to the F2 and F4 stages [36].…”