Display Settings:

Format

Send to:

Choose Destination
Hepatology. 2013 Mar;57(3):1005-16. doi: 10.1002/hep.26107. Epub 2013 Feb 12.

The role of CCAAT enhancer-binding protein homologous protein in human immunodeficiency virus protease-inhibitor-induced hepatic lipotoxicity in mice.

Author information

  • 1Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0678, USA.

Abstract

Human immunodeficiency virus (HIV) protease inhibitors (HIV PIs) are the core components of highly active antiretroviral therapy, which has been successfully used in the treatment of HIV-1 infection in the past two decades. However, benefits of HIV PIs are compromised by clinically important adverse effects, such as dyslipidemia, insulin resistance, and cardiovascular complications. We have previously shown that activation of endoplasmic reticulum (ER) stress plays a critical role in HIV PI-induced dys-regulation of hepatic lipid metabolism. HIV PI-induced hepatic lipotoxicity is closely linked to the up-regulation of CCAAT enhancer binding protein homologous protein (CHOP) in hepatocytes. To further investigate whether CHOP is responsible for HIV PI-induced hepatic lipotoxicity, C57BL/6J wild-type (WT) or CHOP knockout (CHOP(-/-) ) mice or the corresponding primary mouse hepatocytes were used in this study. Both in vitro and in vivo studies indicated that HIV PIs (ritonavir and lopinavir) significantly increased hepatic lipid accumulation in WT mice. In contrast, CHOP(-/-) mice showed a significant reduction in hepatic triglyceride accumulation and liver injury, as evidenced by hematoxylin and eosin and Oil Red O staining. Real-time reverse-transcriptase polymerase chain reaction and immunoblotting data showed that in the absence of CHOP, HIV PI-induced expression of stress-related proteins and lipogenic genes were dramatically reduced. Furthermore, tumor necrosis factor alpha and interleukin-6 levels in serum and liver were significantly lower in HIV PI-treated CHOP(-/-) mice, compared to HIV PI-treated WT mice. Conclusion: Taken together, these data suggest that CHOP is an important molecular link of ER stress, inflammation, and hepatic lipotoxicity, and that increased expression of CHOP represents a critical factor underlying events leading to hepatic injury. (HEPATOLOGY 2013).

Copyright © 2012 American Association for the Study of Liver Diseases.

PMID:
23080229
[PubMed - indexed for MEDLINE]
PMCID:
PMC3566321
Free PMC Article

Images from this publication.See all images (8)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for John Wiley & Sons, Inc. Icon for PubMed Central
    Loading ...
    Write to the Help Desk