期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 397, 期 4, 页码 917-931出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2010.02.016
关键词
HBx; NF-kappa B; TNFR1; steatosis; apoptosis
资金
- Korean National Institutes of Health [4845-300-210-13]
Hepatitis B virus X (HBx) protein is an important regulator of hepatic steatosis observed in patients with hepatitis B virus; however, its underlying molecular mechanism remains unclear. TNF receptor 1 (TNFR1) is an essential pathway for the HBx-mediated nuclear factor kappa B (NF-kappa B) activation involved in hepatic liver injury. Here, we show that HBx-mediated steatosis and apoptosis are regulated by TNFR1- and NF-kappa B-dependent pathways. HBx-mediated tumor necrosis factor alpha (TNF-alpha) production and NF-kappa B activation were completely diminished in anti-TNF alpha-treated cells and TNF-alpha(-/-) or TNFR1(-/-) mice. HBx and TNFR1, which are potentiated by TNF-alpha, are physically associated and colocalize in the plasma membrane. Similarly, TNFR1 depletion inhibits lipid droplets, and lipogenic genes such as sterol regulatory element binding protein (SREBP) 1 and peroxisome proliferator-activated receptor (PPAR) gamma increased in HBx-Tg mice and HepG2-GFPHBx stable cells. Furthermore, lipid accumulation and expression of SREBP1c and PPAR gamma are significantly increased in AdHBx-GFP-injected (intravenous) wild-type mice, but not in TNFR1(-/-) mice. HBx-enhanced transcriptional activities of SREBP1 and PPAR gamma are significantly attenuated by the NF-kappa B inhibitor Bay 11-7082, as well as by TNFR1 depletion. Also, AdHBx-GFP potentiates TNF-alpha-induced apoptosis, which is completely inhibited in TNFR1-depleted cells. Our results suggest that HBx-induced NF-kappa B activation was mediated by direct interaction with TNFR1 and thereby induced TNF-alpha production. HBx-induced NF-kappa B activation is also associated with the induction of hepatic steatosis and apoptosis, which is determined by a TNFR1-dependent pathway. (C) 2010 Elsevier Ltd. All rights reserved.
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