Hepatitis B virus X protein sensitizes primary mouse hepatocytes to ethanol- and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism.
It is well-documented that alcohol drinking together with hepatitis viral infection accelerates liver injury; however the underlying mechanisms remain unknown. In this paper, we demonstrated that primary hepatocytes from transgenic mice overexpressing hepatitis B virus X protein (HBX) were more susceptible to ethanol- and TNF-alpha-induced apoptotic killing. Compared to normal control mouse hepatocytes, ethanol and/or TNF-alpha treatment led to a significant increase in reactive oxygen species, mitochondrial permeability transition, cytochrome C release, caspase-3 activity, and poly (ADP-ribose) polymerase degradation in hepatocytes from HBX transgenic mice. Blocking caspase-3 activity antagonized ethanol- and TNF-alpha-induced apoptosis in primary hepatocytes from HBX transgenic mice. Taken together, our findings suggest that HBX sensitizes primary mouse hepatocytes to ethanol- and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism, which may partly explain the synergistic effects of alcohol consumption and hepatitis B virus infection on liver injury.
Kim
Won Ho
WH
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. jhkwh@hannail.net
Hong
Feng
F
Jaruga
Barbara
B
Zhang
Zheng Sheng
ZS
Fan
Sai Jun
SJ
Liang
T Jake
TJ
Gao
Bin
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D000431:Ethanol / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D054334:Viral Regulatory and Accessory Proteins
D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D000431:Ethanol; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases