In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C.
In hepatocytes, the accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and the unfolded protein response (UPR), mediated by the ER-resident stress sensors ATF-6, IRE1, and PERK. UPR-responsive genes are involved in the fate of ER-stressed cells. Cells carrying hepatitis C virus (HCV) subgenomic replicons exhibit in vitro ER stress and suggest that HCV inhibits the UPR. Since in vivo ER homeostasis is unknown in livers with chronic HCV infection, we investigated ER stress and the UPR in liver samples from untreated patients with chronic hepatitis C (CHC), in comparison with normal livers. Electron microscopy, western blotting, and real-time RT-PCR were used in liver biopsy specimens. Electron microscopy identified features showing ER stress in hepatocyte samples from patients with CHC; however, 'ER-stressed' hepatocytes were found in clusters (3-5 cells) that were scattered in the liver parenchyma. Western blot analysis confirmed the existence of hepatic ER stress by showing activation of the three ER stress sensors ATF-6, IRE1, and PERK in CHC. Real-time RT-PCR showed no significant induction of UPR-responsive genes in CHC. In contrast, genes involved in the control of diffuse processes such as liver proliferation, inflammation, and apoptosis were significantly induced in CHC. In conclusion, livers from patients with untreated CHC exhibit in vivo hepatocyte ER stress and activation of the three UPR sensors without apparent induction of UPR-responsive genes. This lack of gene induction may be explained by the inhibiting action of HCV per se (as suggested by in vitro studies) and/or by our finding of the localized nature of hepatocyte ER stress.
Asselah
Tarik
T
INSERM U773, Centre de Recherche CRB3, Paris, 75018, France. tarik.asselah@bjn.aphp.fr
Bièche
Ivan
I
Mansouri
Abdellah
A
Laurendeau
Ingrid
I
Cazals-Hatem
Dominique
D
Feldmann
Gérard
G
Bedossa
Pierre
P
Paradis
Valérie
V
Martinot-Peignoux
Michelle
M
Lebrec
Didier
D
Guichard
Cécile
C
Ogier-Denis
Eric
E
Vidaud
Michel
M
Tellier
Zéra
Z
Soumelis
Vassili
V
Marcellin
Patrick
P
Moreau
Richard
R
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000328:Adult; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure*; D004722:Endoribonucleases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure*; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D004722:Endoribonucleases; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C403982:ERN2 protein, human