Apotosis in Hepatocytes

Genomic Analysis Reveals a Potential Role for Cell Cycle Perturbation in HCV-Mediated Apoptosis of Cultured Hepatocytes
ArticleRelated ContentComments: 0.Formal Correction: This article has been formally corrected to address the following errors.

To add a note, highlight some text. Hide notes
Make a general comment
Jump to

Abstract
Author Summary
Introduction
Results
Discussion
Materials and Methods
Supporting Information
Acknowledgments
Author Contributions
References
Kathie-Anne Walters1#, Andrew J. Syder2#, Sharon L. Lederer1, Deborah L. Diamond1, Bryan Paeper1, Charles M. Rice2, Michael G. Katze1*

1 Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, United States of America, 2 Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, Rockefeller University, New York, New York, United States of America

Abstract Top
The mechanisms of liver injury associated with chronic HCV infection, as well as the individual roles of both viral and host factors, are not clearly defined. However, it is becoming increasingly clear that direct cytopathic effects, in addition to immune-mediated processes, play an important role in liver injury. Gene expression profiling during multiple time-points of acute HCV infection of cultured Huh-7.5 cells was performed to gain insight into the cellular mechanism of HCV-associated cytopathic effect. Maximal induction of cell-death–related genes and appearance of activated caspase-3 in HCV-infected cells coincided with peak viral replication, suggesting a link between viral load and apoptosis. Gene ontology analysis revealed that many of the cell-death genes function to induce apoptosis in response to cell cycle arrest. Labeling of dividing cells in culture followed by flow cytometry also demonstrated the presence of significantly fewer cells in S-phase in HCV-infected relative to mock cultures, suggesting HCV infection is associated with delayed cell cycle progression. Regulation of numerous genes involved in anti-oxidative stress response and TGF-β1 signaling suggest these as possible causes of delayed cell cycle progression. Significantly, a subset of cell-death genes regulated during in vitro HCV infection was similarly regulated specifically in liver tissue from a cohort of HCV-infected liver transplant patients with rapidly progressive fibrosis. Collectively, these data suggest that HCV mediates direct cytopathic effects through deregulation of the cell cycle and that this process may contribute to liver disease progression. This in vitro system could be utilized to further define the cellular mechanism of this perturbation.

Author Summary Top
Chronic HCV infection is associated with progressive liver injury and subsequent development of fibrosis/cirrhosis. The cellular mechanisms by which HCV replication, and subsequent virus–host interactions, may mediate liver injury are unclear. Microarray experiments were performed to characterize the host transcriptional response to HCV infection of cultured hepatocytes in an attempt to gain insight into the mechanism of HCV-associated cell death. Analysis of the gene expression data revealed that many differentially regulated genes function to induce apoptosis in response to cell cycle arrest, possibly in response to DNA damage and oxidative stress. Labeling of dividing cells in culture followed by flow cytometry also demonstrated the presence of significantly fewer cells in S-phase in HCV-infected cultures relative to mock cultures, suggesting HCV infection is associated with delayed cell cycle progression. Finally, many of the cell-death–related genes whose expression changes in response to HCV infection of cultured hepatocytes were also differentially regulated in liver tissue from HCV-infected patients with histological evidence of fibrosis. In summary, HCV may mediate direct cytopathic effects through perturbation of the cell cycle which potentially contributes to liver disease progression.





And another regrettable thing about death
is the ceasing of your own brand of magic,
which took a whole life to develop and market-
the quips, the witticisms, the slant
adjusted to a few, those loved ones nearest
the lip of the stage, their soft faces blanched
in the footlight glow, their laughter close to tears,
their tears confused with their diamond earrings,
their warm pooled breath in and out with your heartbeat,
their response and your performance twinned.
The jokes over the phone. The memories packed
in rapid-access file. The whole act.
Who will do it again? That's it: no one;
imitators and descendants aren't the same.
- John Updike who passed away on 1/30/09