No evidence of the unfolded protein response in patients with chronic hepatitis C virus infection.
OBJECTIVE
Hepatitis C virus (HCV) proteins activate the unfolded protein response (UPR) in experimental models. The role of the UPR in the pathogenesis of HCV-induced liver injury has not been determined. Our aim was to investigate the role of the UPR in the pathogenesis of chronic HCV.


METHODS
Liver biopsy samples from 124 patients with chronic HCV and 24 HCV/HBV-negative subjects with histologically normal liver (NDL) were assessed. The hepatic mRNA expression of components of the UPR was measured by semi-quantitative real-time polymerase chain reaction. Glucose regulated protein (GRP) 78 protein expression was assessed by immunohistochemistry.


RESULTS
The expression of GRP78 mRNA and growth arrest and damage inducible protein 34 (GADD34) mRNA was significantly lower in subjects with HCV than NDL (P = 0.007 and P < 0.001, respectively). There was no significant difference in the expression of GRP94 mRNA, spliced X box binding protein 1 (sXBP1) mRNA, C/EBP homologous protein mRNA (CHOP) and ER degradation enhancing α-mannosidase-like protein (EDEM) mRNA and GRP78 protein between patients with HCV and NDL. There were no relationships between elements of the UPR and inflammation or fibrosis in patients with HCV.


CONCLUSIONS
Downstream components of UPR were not activated in patients with chronic HCV. Therefore, the UPR may not play a prominent role in liver injury in patients with chronic HCV infection.
Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Stuart
S
McPherson
Elizabeth E
EE
Powell
Helen D
HD
Barrie
Andrew D
AD
Clouston
Michael
M
McGuckin
Julie R
JR
Jonsson
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000328:Adult; D000943:Antigens, Differentiation / Q000235:genetics; D001706:Biopsy; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D016009:Chi-Square Distribution; D004268:DNA-Binding Proteins / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011793:Queensland; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases; D006360:Heat-Shock Proteins; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C497249:DDIT3 protein, human; C000717247:HSPA5 protein, human; C528229:ERN1 protein, human; C087519:PPP1R15A protein, human