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The transcription factor nuclear factor kappa B (NF-κB) is activated in hepatocytes in the pathogenesis of hepatic steatosis. However, the action mechanism of NF-κB remains to be established in the hepatic steatosis. In this study, the P50 subunit of NF-κB was found to promote the hepatic steatosis through regulation of histone deacetylase 1 (HDAC1) in hepatocytes. The activity was supported by the phenotypes of P50 knockout (P50-KO) mice and P65 knockout (P65-KO) mice. Hepatic steatosis was reduced in the P50-KO mice, but not in the P65-KO mice. The reduction was a result of inhibition of HDAC1 activity in the P50-KO cells. Knockdown of Hdac1 gene led to suppression of hepatocyte steatosis in HepG2 cells. A decrease in sterol-regulatory element binding protein 1c (SREBP1c) protein was observed in the liver of P50-KO mice and in cell with Hdac1 knockdown. The decrease was associated with an increase in succinylation of SREBP1c protein. The study suggests that P50 stabilizes HDAC1 to support the SREBP1c activity in hepatic steatosis in the pathophysiological condition. Interruption of this novel pathway in the P50-KO, but not the P65-KO mice, may account for the difference in hepatic phenotypes in the two lines of transgenic mice., Graphical abstract NF-κB promotes hepatic steatosis through an impact of P50 subunit in HDAC1 protein. P50 stabilizes HDAC1 protein to keep succinylation of SREBP1c under control in favor of lipogenesis in the liver of wild type or P65-KO mice. This pathway failed to operate in P50-KO mice leading to reduction of hepatic steatosis.Image 1

Background: Mucosal epithelial apoptosis with non-specific inflammation is an essential pathological characteristic in portal hypertensive gastropathy (PHG). However, whether a coordinated crosstalk between myeloid cells and epithelial cells involved in PHG remains unclear. Methods: Gastric injury and mucosal apoptosis were examined in patients with PHG and the PHG model of p65ΔM/ΔM (myeloid cells specific NF-κBp65 deletion) and p65f/f (floxed p65) mice, PUMA-WT (PUMA wild-type) and PUMA-KO (PUMA knockout) mice. The interaction of IL-6, Fas, FasL, NF-κBp65 and PUMA expression was investigated, and the mechanisms underlying IL-6-regulated gastric epithelial apoptosis were analysed. Findings: IL-6, which is induced in the mucosa of PHG patients and mice, promotes FasL production via enhancing NF-κBp65 activation in myeloid cells, while blockage of IL-6 signaling by Tocilizumab or deletion of NF-κBp65 in myeloid cells attenuates the inflammatory response and Fas/FasL-mediated epithelial apoptosis in PHG. IL-6-driven FasL from myeloid cells combines with epithelial Fas receptor to encourage NF-κBp65/PUMA-mediated epithelial apoptosis in PHG, and inhibition of NF-κBp65 or knockout of PUMA dramatically alleviates Fas/FasL network-mediated epithelial apoptosis in PHG. Interpretation: These results indicate that IL-6 drives FasL generation via NF-κBp65 in myeloid cells to promote Fas/NF-κBp65/PUMA-mediated epithelial apoptosis in PHG. Funding: This work was supported by grants from the National Natural Science Foundation of China (U1501224, 81700536), the Natural Science Foundation Team Project of Guangdong Province (2018B03031200), the Science and Technology Developmental Special Foundation of Guangdong Province (2017B020226003), the Basic Research Programme of Young Teachers' Training Project of Sun Yat-sen University (17ykpy51), the Science and Technology Planning Projects of Guangzhou City (201604020118, 201604020002). Declaration of Interest: The authors declare that there are no conflicts of interest. Ethical Approval: The study protocol and the acquisition of the tissue samples were approved by the Institutional Review Board of The Third Affiliated Hospital of Sun Yat-Sen University.

G-protein-coupled receptors (GPCR) constitute the largest known superfamily for signal transduction and transmission, and they control a variety of physiological and pathological processes. GPCR adaptor β-arrestins (ARRBs) play a role in cancerous proliferation. However, the effect of ARRBs in inflammation-mediated hepatocellular carcinogenesis is unknown. Here we show that ARRB1, but not ARRB2, is upregulated in inflammation-associated hepatocellular carcinoma (HCC) and paracancerous tissues in humans. A genotoxic carcinogen, diethylnitrosamine (DEN), significantly induces hepatic inflammation, TNF-α production and ARRB1 expression. Although ARRB1 deficiency does not affect hepatic inflammation and TNF-α production, it markedly represses hepatocellular carcinogenesis by suppressing malignant proliferation in DEN-treated mice. Furthermore, TNF-α directly induces hepatic ARRB1 expression and enhances ARRB1 interaction with Akt by binding to boost Akt phosphorylation, resulting in malignant proliferation of liver cells. Our data suggest that ARRB1 enhances hepatocellular carcinogenesis by inflammation-mediated Akt signalling and that ARRB1 may be a potential therapeutic target for HCC.