Inhibition of hepatocyte nuclear factor 4 transcriptional activity by the nuclear factor {kappa}B pathway

Varvara Nikolaidou-Neokosmidou , Vassilis I Zannis , Dimitris Kardassis (1)

1 Medicine

Hepatocyte Nuclear Factor 4 (HNF-4) is a key regulator of liver specific gene expression in mammals. We have shown previously that the activity of the human apolipoprotein C-III (APOC3) promoter is positively regulated by the anti-inflammatory cytokine Transforming Growth Factor {beta} (TGF{beta}) and its effectors Smad3 and Smad4 proteins via physical and functional interactions between Smads and HNF-4. We now show that the pro-inflammatory cytokine Tumor Necrosis Factor {alpha} (TNF{alpha}) antagonizes TGF{beta} for the regulation of APOC3 gene expression in hepatocytes. TNF{alpha} was a strong inhibitor of the activity of apolipoprotein promoters that harbor HNF-4 binding sites and this inhibition required HNF-4. Using specific inhibitors of TNF{alpha}-induced signaling pathways it was shown that inhibition of the APOC3 promoter by TNF{alpha} involved Nuclear Factor {kappa} B (NF-{kappa}B). Latent Membrane Protein 1 of Epstein Barr Virus which is an established, potent activator of NF-{kappa}B as well as wild type forms of various NF-{kappa}B signaling mediators also inhibited strongly the APOC3 promoter and the transactivation function of HNF-4. TNF{alpha} had no effect on the stability or the nuclear localization of HNF-4 in HepG2 cells but inhibited the binding of HNF-4 to the proximal APOC3 HRE. Using the GAL4 system, we showed that both Activation Functions of HNF-4 (AF-1 and AF-2) are inhibited by TNF{alpha} and that this inhibition was abolished by overexpression of different HNF-4 coactivators including PGC-1, CBP and SRC3. In summary, our findings indicate that TNF{alpha} or other factors that trigger an NF-{kappa}B response in hepatic cells inhibit the transcriptional activity of the APOC3 and other HNF-4-dependent promoters and that this inhibition could be accounted for by a reduction in DNA binding and the downregulation of the transactivation potential of the AF-1 and AF-2 domains of HNF-4.

Mots clés: Life Sciences

Varvara Nikolaidou-Neokosmidou, Vassilis I Zannis, Dimitris Kardassis. Inhibition of hepatocyte nuclear factor 4 transcriptional activity by the nuclear factor {kappa}B pathway. Biochemical Journal, 2006, 398 (3), pp.439-450. ⟨10.1042/BJ20060169⟩. ⟨hal-00478524⟩