No abstract

HBV (hepatitis B virus) is a primary cause of chronic liver disease, which frequently results in hepatitis, cirrhosis and ultimately HCC (hepatocellular carcinoma). Recently, we showed that HBx (HBV protein X) expression induces lipid accumulation in hepatic cells mediated by the induction of SREBP1 (sterol-regulatory-element-binding protein 1), a key regulator of lipogenic genes in the liver. However, the molecular mechanisms by which HBx increases SREBP1 expression and transactivation remain to be clearly elucidated. In the present study, we demonstrated that HBx interacts with LXRalpha (liver X receptor alpha) and enhances the binding of LXRalpha to LXRE (LXR-response element), thereby resulting in the up-regulation of SREBP1 and FAS (fatty acid synthase) in the presence or absence of the LXR agonist T0901317 in the hepatic cells and HBx-transgenic mice. Furthermore, HBx also augments the ability to recruit ASC2 (activating signal co-integrator 2), a transcriptional co-activator that controls liver lipid metabolic pathways, to the LXRE with LXRalpha. These studies place LXRalpha in a key position within the HBx-induced lipogenic pathways, and suggest a molecular mechanism through which HBV infection can stimulate the SREBP1-mediated control of hepatic lipid accumulation.

SHP (short heterodimer partner) is an orphan nuclear receptor that plays an important role in regulating glucose and lipid metabolism. A variety of transcription factors are known to regulate transcription of the PEPCK (phosphoenolpyruvate carboxykinase) gene, which encodes a rate-determining enzyme in hepatic gluconeogenesis. Previous reports identified glucocorticoid receptor and Foxo1 as novel downstream targets regulating SHP inhibition [Borgius, Steffensen, Gustafsson and Treuter (2002) J. Biol. Chem. 277, 49761-49796; Yamagata, Daitoku, Shimamoto, Matsuzaki, Hirota, Ishida and Fukamizu (2004) J. Biol. Chem. 279, 23158-23165]. In the present paper, we show a new molecular mechanism of SHP-mediated inhibition of PEPCK transcription. We also show that the CRE1 (cAMP regulatory element 1; -99 to -76 bp relative to the transcription start site) of the PEPCK promoter is also required for the inhibitory regulation by SHP. SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. Taken together, these results suggest that SHP might regulate a level of hepatic gluconeogenesis driven by C/EBPalpha activation.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and chronic hepatitis B virus (HBV) infection is the most common risk factor for HCC. The HBV proteins can induce oncogenic or synergy effects with a hyperproliferative response on transformation into HCC. CREBH (cAMP-responsive, element-binding protein H), activated by stress in the endoplasmic reticulum (ER), is an ER-resident transmembrane bZIP (basic leucine zipper) transcription factor that is specifically expressed in the liver. In the present study, we address the role played by CREBH activated by ER stress in HBV-induced hepatic cell proliferation. We confirmed CREBH activation by ER stress and showed that it occurred as a result of/via hepatitis B virus X (HBx)-induced ER stress. CREBH activated by HBx increased the expression of AP-1 target genes through c-Jun induction. Under pathological conditions such as liver damage or liver regeneration, activated CREBH may have an important role to play in hepatic inflammation and cell proliferation, as an insulin receptor with dual functions under these conditions. We showed that CREBH activated by HBx interacted with HBx protein, leading to a synergistic effect on the expression of AP-1 target genes and the proliferation of HCC cells and mouse primary hepatocytes. In conclusion, in HBV-infected hepatic cells or patients with chronic HBV, CREBH may induce proliferation of hepatic cells in co-operation with HBx, resulting in HCC.

Stromal cell-derived factor-1 (SDF-1/CXCL12) is one of the essential chemokines, which mediates hematopoietic differentiations. However, the mechanism by which SDF-1 expression is regulated in granulocyte differentiation is poorly understood. Here, we suggest a novel mechanism by which all-trans-retinoic acid (ATRA) induces the expression of SDF-1 during the differentiation of promyelomonocytic leukemic U937 cells. Moreover, we also demonstrate that activation of transcription factor C/EBPbeta by ATRA regulates SDF-1 expression in U937 cells. In addition, we show that the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and Pyk2 are up-regulated by SDF-1 and increased markedly by the costimulation of ATRA and SDF-1. Furthermore, ATRA and SDF-1alpha additively induce U937 cell differentiation. Indeed, silencing the expression of SDF-1 inhibits ATRA-induced granulocyte differentiation significantly. Taken together, these results indicate that SDF-1alpha is involved in granulocyte differentiation in response to ATRA, mediated by the activation of the transcription factor C/EBPbeta.