HBx-induced hepatic steatosis and apoptosis are regulated by TNFR1- and NF-kappaB-dependent pathways.
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 kappaB (NF-kappaB) activation involved in hepatic liver injury. Here, we show that HBx-mediated steatosis and apoptosis are regulated by TNFR1- and NF-kappaB-dependent pathways. HBx-mediated tumor necrosis factor alpha (TNF-alpha) production and NF-kappaB 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-kappaB 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-kappaB activation was mediated by direct interaction with TNFR1 and thereby induced TNF-alpha production. HBx-induced NF-kappaB activation is also associated with the induction of hepatic steatosis and apoptosis, which is determined by a TNFR1-dependent pathway.
Division of Metabolic Diseases, Center for Biomedical Sciences, National Institutes of Health, 194 Tongillo, Eunpyeong-gu, Seoul 122-701, Korea.
Ji Yeon
JY
Kim
Eun Hyun
EH
Song
Hyun Jung
HJ
Lee
Yeo Kyoung
YK
Oh
Kyung-Hee
KH
Choi
Dae-Yeul
DY
Yu
Sang Ick
SI
Park
Je-Kyung
JK
Seong
Won-Ho
WH
Kim
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D005234:Fatty Liver; D006515:Hepatitis B virus / Q000472:pathogenicity*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000276:immunology*; D015534:Trans-Activators / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
D052002:NF-kappa B p50 Subunit; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C073701:Nfkb1 protein, mouse