HBx-Induced hepatic steatosis and apoptosis are regulated by TNFR1- and NF-κB-dependent pathways

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HBx-Induced hepatic steatosis and apoptosis are regulated by TNFR1- and NF-κB-dependent pathways
J Y Kim; E H Song; H J Lee; Y K Oh; K H Choi; Dae Yeul Yu; S I Park; J K Seong; W H Kim
Bibliographic Citation
Journal of Molecular Biology, vol. 397, no. 4, pp. 917-931
Publication Year
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 κB (NF-κB) activation involved in hepatic liver injury. Here, we show that HBx-mediated steatosis and apoptosis are regulated by TNFR1- and NF-κB-dependent pathways. HBx-mediated tumor necrosis factor α (TNF-α) production and NF-κB activation were completely diminished in anti-TNF-α-treated cells and TNF-α-/- or TNFR1-/- mice. HBx and TNFR1, which are potentiated by TNF-α, 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) γ increased in HBx-Tg mice and HepG2-GFPHBx stable cells. Furthermore, lipid accumulation and expression of SREBP1c and PPARγ are significantly increased in AdHBx-GFP-injected (intravenous) wild-type mice, but not in TNFR1-/- mice. HBx-enhanced transcriptional activities of SREBP1 and PPARγ are significantly attenuated by the NF-κB inhibitor Bay 11-7082, as well as by TNFR1 depletion. Also, AdHBx-GFP potentiates TNF-α-induced apoptosis, which is completely inhibited in TNFR1-depleted cells. Our results suggest that HBx-induced NF-κB activation was mediated by direct interaction with TNFR1 and thereby induced TNF-α production. HBx-induced NF-κB activation is also associated with the induction of hepatic steatosis and apoptosis, which is determined by a TNFR1-dependent pathway.
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