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


CONCLUSIONS
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).
Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0678, USA.
Yun
Y
Wang
Luyong
L
Zhang
Xudong
X
Wu
Emily C
EC
Gurley
Elaine
E
Kennedy
Phillip B
PB
Hylemon
William M
WM
Pandak
Arun J
AJ
Sanyal
Huiping
H
Zhou
D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000503:physiopathology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism
C497250:Ddit3 protein, mouse; D017320:HIV Protease Inhibitors; D051742:Transcription Factor CHOP