title: New Mechanism of Hepatic Fibrogenesis: Hepatitis C Virus Infection Induces Transforming Growth Factor β1 Production through Glucose-Regulated Protein 94.
abstract: Hepatitis C virus (HCV) is one of the leading causes of chronic liver inflammatory disease (hepatitis), which often leads to more severe diseases, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver fibrosis, in particular, is a major pathogenic consequence of HCV infection, and transforming growth factor β1 (TGF-β1) plays a key role in its pathogenesis. Several HCV proteins have been suggested to either augment or suppress the expression of TGF-β1 by HCV-infected cells. Here, we report that TGF-β1 levels are elevated in HCV-infected hepatocytes cultured in vitro and in liver tissue of HCV patients. Notably, the level of TGF-β1 in media from in vitro-cultured HCV-infected hepatocytes was high enough to activate primary hepatic stellate cells isolated from rats. This indicates that TGF-β1 secreted by HCV-infected hepatocytes is likely to play a key role in the liver fibrosis observed in HCV patients. Moreover, we showed that HCV E2 protein triggers the production of TGF-β1 by HCV-infected cells through overproduction of glucose-regulated protein 94 (GRP94).
  
  
  OBJECTIVE
  Hepatic fibrosis is a critical step in liver cirrhosis caused by hepatitis C virus infection. It is already known that immune cells, including Kupffer cells, mediate liver fibrosis. Recently, several papers have suggested that HCV-infected hepatocytes also significantly produce TGF-β1. Here, we provide the first examination of TGF-β1 levels in the hepatocytes of HCV patients. Using an HCV culture system, we showed that HCV infection increases TGF-β1 production in hepatocytes. Furthermore, we confirmed that the amount of TGF-β1 secreted by HCV-infected hepatocytes was sufficient to activate primary hepatic stellate cells. To understand the molecular basis of TGF-β1 production in HCV-infected hepatocytes, we used HCV replicons and various stable cell lines. Finally, we elucidated that HCV E2 triggered TGF-β1 secretion via GRP94 mediated NF-κB activation. This study contributes to the understanding of liver fibrosis by HCV and suggests a new potential target (GRP94) for blocking liver cirrhosis in HCV patients.
authors.affiliation: POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Min Hyeok
authors.initials: MH
authors.lastname: Jee
authors.affiliation: POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Ka Young
authors.initials: KY
authors.lastname: Hong
authors.affiliation: POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Kim
authors.affiliation: POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Song Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea sungkey@postech.ac.kr.
authors.forename: Sung Key
authors.initials: SK
authors.lastname: Jang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016174:Hepacivirus / Q000502:physiology*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000502:physiology; D006526:Hepatitis C / Q000150:complications; D022781:Hepatocytes / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*; D014759:Viral Envelope Proteins / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D008562:Membrane Glycoproteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014759:Viral Envelope Proteins; C053387:endoplasmin; C091015:glycoprotein E2, Hepatitis C virus