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536A AASLD ABSTRACTS HEPATOLOGY, October, 2015 prevent the recurrence and development of HCC after surgical removal of the primary tumors. Previous in vitro experiments showed that ACR selectively suppresses the growth of human HCC cells (JHH7, HuH7, and HepG2) but not normal human hepatic cells (Hc). In the present study, the genome-wide transcriptome analysis was performed to identify a biomarker for ACR treatment of HCC. Method: Differential gene expression profiles of JHH7 and Hc cells treated with ACR were measured using the next-generation sequencing-based Cap Analysis Gene Expression (CAGE) analysis. Inhibitory effect of ACR on MYCN expression was confirmed by real-time PCR in culture cells, animal models and liver biopsy of HCC patients administered with ACR (n = 6). MYCN-dependent signaling pathways underlying the growth suppression by ACR were explored using knowledge-based ingenuity pathway analysis (IPA), RNA interference, chemical inhibitors and luciferase assays. Relationship between MYCN levels and tumor recurrence in HCC patients (n = 102) was evaluated using the log-rank test. Correlations between MYCN and liver cancer stem cell (CSC) markers were determined using Pearson correlation coefficients based on microarray database or in patients. Results: MYCN was expressed in JHH7 cells but not in Hc cells, and inhibited by ACR but not by its ethyl analogues that showed no growth suppression. ACR also selectively suppressed the growth of MYCN-positive neuroblastoma cells, but not that negative for MYCN. Four out of 6 liver biopsies of HCC patients (66.7%) who had received 8 weeks of ACR (600 mg/day) after definitive treatment showed decreased MYCN expression (< 0.5- fold). The result of IPA suggested a Sp1/MYCN/caspase-8 signaling pathway underlying ACR’s anticancer effect. Upon knockdown of MYCN, HCC cells showed suppressed cell growth and increased caspase-8 activity. An Sp1 inhibitor suppressed MYCN expression, whereas a caspase-8 inhibitor restored ACR-induced growth suppression. Finally, clinical analysis indicated that MYCN expression in HCC tumors was significantly correlated with CSC markers AFP, EpCAM and CD133 but not CD90, and negatively associated with recurrence of early-stage HCC. Conclusion: MYCN is a new biomarker of eligibility for ACR treatment that correlates with liver CSC with progenitor features and poor prognosis of HCC. ACR suppressed HCC cell growth through a Sp1/MYCN/ caspase-8 dependent signaling pathway. Disclosures: Naoto Ishibashi - Employment: KOWA Company, LTD. The following authors have nothing to disclose: Soichi Kojima, Xian-Yang Qin, Harukazu Suzuki, Masao Honda, Goshi Shiota, Hisataka Moriwaki, Masahito Shimizu 658 Farnesoid X Receptor (FXR) Activation by Bile Salts and FXR Agonists Increases the Hepatic Expression of the Unfolded Protein Response Regulator X-box Binding Protein 1 Spliced (XBP1s) Xiaoying Liu, David Hilburn, Seong W. Park, Brian E. LeCuyer, Richard M. Green; Northwestern University, Chicago, IL The Unfolded Protein Response (UPR) is an adaptive response to endoplasmic reticulum stress that occurs in cholestatic and other forms of liver disease. X-box binding protein 1 spliced (XBP1s) is a highly conserved regulator of the UPR, and is formed by an unconventional splicing mechanism that removes 26 nucleotides from the unspliced XBP1 mRNA. The farnesoid X receptor (FXR) is a nuclear bile acid receptor which regulates bile acid metabolism, and FXR agonists may provide novel therapies for cholestatic and fatty liver diseases. In this study, we demonstrate a novel role of FXR in regulating liver XBP1 splicing and XBP1s expression. Methods: Male FVB mice (8-12 weeks) were fed chow supplemented with 0.3% sodium deoxycholate (DCA), an endogenous FXR bile salt ligand, for up to 7 days. Huh7/NTCP or HepG2 cells were treated with either bile salts (GCDCA, TCDCA, TDCA and TUDCA) or the synthetic FXR agonists obeticholic acid (OCA) and GW4064 for 4-8 hours. These cells were also co- treated with the FXR antagonist guggulsterone, and either FXR siRNA or control siRNA. Gene and protein expression was analyzed by qPCR and Western blotting. XBP1 splicing activity was measured using an XBP1-luciferase reporter construct that assays the 26-nt atypical splicing of the XBP1 mRNA. Results: Hepatic XBP1s and its downstream target ERdj4 mRNA expression increased 6.5-fold (P < 0.05) and 1.7-fold (P < 0.05) in mouse livers after DCA feeding for 1 and 3 days, respectively. GCDCA (50 μM), TCDCA (10 μM) and TDCA (10 μM) treatment increased XBP1s protein expression in Huh7/NTCP cells, while TUDCA (10 μM) had no effect. The synthetic FXR agonists OCA (2.5 μM) and GW4064 (2.5 μM) also induced XBP1s mRNA and protein expression. XBP1s protein induction by FXR agonists was blocked by the FXR antagonist guggulsterone (50 μM) and by FXR siRNA. The FXR agonists TCDCA (100 μM) and GW4064 (10 μM) also increased XBP1 splicing-luciferase activity 2 and 4-fold, respectively compared to controls (P < 0.001). Conclusions: DCA bile salt feeding to mice increases the expression of hepatic XBP1s and its downstream target ERdj4. FXR bile salt ligands and synthetic agonists increase XBP1s expression in Huh7/NTCP or HepG2 cells, while TUDCA has no effect. These effects are due, at least in part, to enhanced XBP1 splicing into XBP1s. Increased XBP1s expression is blocked by the FXR antagonist guggulsterone and by FXR knockdown. We demonstrate the novel finding that a FXR-mediated pathway increases the expression of liver XBP1s. We speculate that this may be important in the pathogenesis of cholestatic and fatty liver diseases. Disclosures: Richard M. Green - Consulting: McNeil The following authors have nothing to disclose: Xiaoying Liu, David Hilburn, Seong W. Park, Brian E. LeCuyer 659 Cerium oxide nanoparticle treatment enhances liver regeneration after two-thirds partial hepatectomy in rats Manuel Morales-Ruiz 1,3 , Altamira Arce-Cerezo 1,5 , Montserrat Pauta 1,5 , Jordi Ribera 1,3 , Denise Oró 1,3 , Gregori Casals 1,3 , Guillermo Fernández-Varo 1,3 , Tetyana Yudina 4 , Víctor Puntes 4 , Wladimiro Jiménez 1,2 ; 1 Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain; 2 Department of Physiological Sciences I, IDIBAPS, CIBERehd, University of Barcelona School of Medicine, Barcelona, Spain; 3 IDIBAPS, CIBERehd, Barcelona, Spain; 4 Catalan Institute of Nanoscience and Nanotechnology, UAB, Bellaterra, Spain; 5 IDIBAPS, Barcelona, Spain Introduction and aim: Several <strong>studies</strong> have shown that oxidative stress impairs hepatic regeneration in mice. Therefore, testing new anti-oxidant drugs to improve liver regeneration has clinical interest. Recently, considerable attention has been paid to cerium oxide nanoparticles (CeO 2 NPs) as a treatment for oxidative stress-related diseases. This interest relies on the multi-enzyme mimetic properties of CeO 2 NPs that turn these nanoparticles into an effective scavenger of reactive oxygen species. Consequently, we aimed to investigate the effect of CeO 2 NPs treatment on hepatic regeneration after partial hepatectomy. Methods: CeO 2 NPs (4 nm in size), were synthesized by precipitation of a cerium (III) salt by the addition of ammo-
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 537A nium salt tetramethylammonium-hydroxide (TmaOH). Forty-four male Wistar rats were divided equally into two groups. In the first group, rats were treated with 0.1 mg/kg CeO 2 NPs i.v. twice a week for two weeks before 2/3 partial hepatectomy (PHx). The second group received vehicle as a control treatment. PHx was performed in both experimental groups and rats were sacrificed at different time points for further analysis. Results: Rats were sacrificed at day 6 after PHx and the ratio “liver remnant weight/total body weight” was calculated to obtain the liver regenerative index. Rats treated with CeO 2 NPs showed a significant 11% increase in liver regeneration, compared with vehicle treated rats (p
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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1366A CATEGORY INDEX HEPATOLOGY, Oc
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