S.K. Yoon

Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis

In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease. Please see later in the article for the Editors Summary

Oleuropein attenuates hepatic steatosis induced by high-fat diet in mice

BACKGROUND & AIMSnOleuropein, a secoiridoid derived from olives and olive oil, has been known to possess antimicrobial, antioxidative, and anticancer activities. The purpose of the present study was to determine whether oleuropein has a protective effect against hepatic steatosis induced by a high fat diet (HFD) and to elucidate its underlying molecular mechanisms in mice.nnnMETHODSnMale C57BL/6N mice were fed a normal diet (ND), HFD, or an oleuropein-supplemented diet (OSD) for 10 weeks. The plasma and hepatic lipid levels were determined, and the hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively.nnnRESULTSnThe supplementation of HFD with oleuropein reversed the HFD-induced increases in liver weight along with plasma and hepatic lipid levels in mice. The expression of Wnt10b inhibitor genes, such as secreted firizzed-related sequence protein 5 and dickkopf homolog 2, was downregulated, whereas the β-catenin protein expression was upregulated in the liver of OSD-fed mice compared to HFD-fed mice. Fibroblast growth factor receptor 1 (FGFR1), phosphoextracellular-signal-regulated kinase 1/2, cyclin D, and E2F transcription factor 1, along with several key transcription factors and their target genes involved in adipogenesis, were downregulated by oleuropein. OSD-fed mice exhibited decreased expression of the toll-like-receptor-(TLR)-mediated signaling molecules (TLR2, TLR4, and myeloid differentiation primary-response gene 88) and proinflammatory cytokines, in their livers, as compared to HFD mice.nnnCONCLUSIONSnThese results suggest that the protective effects of oleuropein against HFD-induced hepatic steatosis in mice appear to be associated with the Wnt10b- and FGFR1-mediated signaling cascades involved in hepatic lipogenesis, along with the TLR2- and TLR4-mediated signaling implicated in hepatic steatosis.

Hepatitis C Virus Infection Is Blocked by HMGB1 Released from Virus-Infected Cells

ABSTRACT High-mobility group box 1 (HMGB1), an abundant nuclear protein that triggers host immune responses, is an endogenous danger signal involved in the pathogenesis of various infectious agents. However, its role in hepatitis C virus (HCV) infection is not known. Here, we show that HMGB1 protein is translocated from the nucleus to cytoplasm and subsequently is released into the extracellular milieu by HCV infection. Secreted HMGB1 triggers antiviral responses and blocks HCV infection, a mechanism that may limit HCV propagation in HCV patients. Secreted HMGB1 also may have a role in liver cirrhosis, which is a common comorbidity in HCV patients. Further investigations into the roles of HMGB1 in the diseases caused by HCV infection will shed light on and potentially help prevent these serious and prevalent HCV-related diseases.

Piperine, an LXRα antagonist, protects against hepatic steatosis and improves insulin signaling in mice fed a high-fat diet

This study investigated the role of piperine in the transcriptional regulation of liver X receptor α (LXRα) and the effects of dietary piperine on high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in mice. Furthermore, we explored the potential molecular mechanisms through which the protective effects of piperine may work. In the present study, piperine significantly reduced ligand-induced LXRα activity in a dose-dependent manner and gradually disrupted the interaction between ligand-bound LXRα and GST-CBP. In mice, an HFD supplemented with 0.05% piperine (PSD) significantly decreased body and liver weight as well as plasma and hepatic lipid levels. In agreement with our in vitro study, in mice fed an HFD, dietary piperine markedly decreased LXRα mRNA expression and its lipogenic target genes (i.e., SREBP1c, ChREBPα, FAS, and CD36). Piperine also significantly decreased plasma insulin and glucose concentrations, while increasing insulin sensitivity in mice fed an HFD. In addition, piperine downregulated the expression of genes involved in ER stress, including GRP78, activating transcription factor 6, and eukaryotic translation initiation factor 2α, and upregulated GLUT2 translocation from the cytosol to the plasma membrane in the livers of PSD mice. Piperine antagonized LXRα transcriptional activity by abolishing the interaction of ligand-bound LXRα with the co-activator CBP. The effects of piperine on hepatic lipid accumulation were likely regulated via alterations in LXRα-mediated lipogenesis in mice fed an HFD. Dietary piperine also led to reduced ER stress and increased insulin sensitivity and prevented hepatic insulin resistance in mice fed the HFD.

Predictive Factors for Beneficial Response to Interferon-alfa Therapy in Chronic Hepatitis C

Objectives: Interferon is the only established teatment for chronic hepatitis C but the host-dependent or virus-related factors affecting the response rate to interferon therapy are not yet dear. The purpose of this study was to investigate the factors predictive of response to interferon-alfa therapy in chronic hepatitis C. Methods: Twenty-five consecutive patients with chronic hepatitis C were randomized to three regimens of interferon-alfa: group A (n=7, 3MU every day for 3 months), group B (n=8, 3MU every other day for 3 months) and group C (n=10, 3MU every other day for 6 months), We quantified serum HC RNA levels by competitive reverse transcription-polymerase chain reaction (RT-PCR)and performed HCV genotyping using type-specific primers deduced from the NS5 region of the HCV genome. We also attempted to identify which demographic, biochemical and histologic factors in addition to virus-related factors would significantly predict beneficial response to interferon by multivariate analysis. Results: Sustained responders were 8 (36.4%), nonsustained responders were 2 (9.1%) and nonresponders were 12 (54.5%) of 22 patients who had received complete therapy. The initial HCV RNA level (logarithmic transformed copy numbers per ml of serum)in sustained responders (5.75±0.39) was significantly lower than that of nonsustained responders (6.80±0.71)and nonresponders (6.70±0.52) (p<0.05). In multivariate multiple logistic regression analysis, the serum HCV RNA level before therapy was only the independent predictor of a sustained response to interferon-alfa therapy (p=0.001). Conclusions: Serum HCV RNA level before therapy was the most useful predictor of a sustained response to interferon-alfa therapy for chronic hepatitis C.

RAR-Related Orphan Receptor Gamma (ROR-γ) Mediates Epithelial-Mesenchymal Transition of Hepatocytes During Hepatic Fibrosis†

The epithelial‐mesenchymal transition (EMT) is involved in many different types of cellular behavior, including liver fibrosis. In this report, we studied a novel function of RAR‐related orphan receptor gamma (ROR‐γ) in hepatocyte EMT during liver fibrosis. To induce EMT in vitro, primary hepatocytes and FL83B cells were treated with TGF‐β1. Expression of ROR‐γ was analyzed by Western blot in the fibrotic mouse livers and human livers with cirrhosis. To verify the role of ROR‐γ in hepatocyte EMT, we silenced ROR‐γ in FL83B cells using a lentiviral short hairpin RNA (shRNA) vector. The therapeutic effect of ROR‐γ silencing was investigated in a mouse model of TAA‐induced fibrosis by hydrodynamic injection of plasmids. ROR‐γ expression was elevated in hepatocyte cells treated with TGF‐β1, and ROR‐γ protein levels were elevated in the fibrotic mouse livers and human livers with cirrhosis. Knockdown of ROR‐γ resulted in the attenuation of TGF‐β1‐induced EMT in hepatocytes. Strikingly, ROR‐γ bound to ROR‐specific DNA response elements (ROREs) in the promoter region of TGF‐β type I receptor (Tgfbr1) and Smad2, resulting in the downregulation of Tgfbr1 and Smad2 after silencing of ROR‐γ. Therapeutic delivery of shRNA against ROR‐γ attenuated hepatocyte EMT and ameliorated liver fibrosis in a mouse model of TAA‐induced liver fibrosis. Overall, our results suggest that ROR‐γ regulates TGF‐β‐induced EMT in hepatocytes during liver fibrosis. We suggest that ROR‐γ may become a potential therapeutic target in treating liver fibrosis. J. Cell. Biochem. 118: 2026–2036, 2017.

1033 COMBINATION THERAPY WITH TRANSARTERIAL CHEMOEMBOLIZATION AND RADIOFREQENCY ABLATION COMPARED WITH TRANSARTERIAL CHEMOEMBOLIZATION OR RFA FOR EARLY HEPATOCELLULAR CARCINOMA

1032 COMPARATIVE STUDY BETWEEN DRUG-ELUTING BEAD (DC BEAD) LOADED WITH DOXORUBICIN (DEBDOX) AND CONVENTIONAL TRANSARTERIAL CHEMOEMBOLIZATION IN THE TREATMENT OF HEPATOCELLULAR CARCINOMA M.J. Song, D.S. Song, S.H. Yoo, H.Y. Kim, C.-H. Park, U.I. Chang, H.J. Chun, S.H. Bae, J.Y. Choi, J.M. Yang, S.K. Yoon. Hepatology and Gastroenterology, Radiology, The Catholic Medical University, Seoul, Republic of Korea E-mail: mjsong95@gmail.com

1032 COMPARATIVE STUDY BETWEEN DRUG-ELUTING BEAD (DC BEAD®) LOADED WITH DOXORUBICIN (DEBDOX) AND CONVENTIONAL TRANSARTERIAL CHEMOEMBOLIZATION IN THE TREATMENT OF HEPATOCELLULAR CARCINOMA

1032 COMPARATIVE STUDY BETWEEN DRUG-ELUTING BEAD (DC BEAD) LOADED WITH DOXORUBICIN (DEBDOX) AND CONVENTIONAL TRANSARTERIAL CHEMOEMBOLIZATION IN THE TREATMENT OF HEPATOCELLULAR CARCINOMA M.J. Song, D.S. Song, S.H. Yoo, H.Y. Kim, C.-H. Park, U.I. Chang, H.J. Chun, S.H. Bae, J.Y. Choi, J.M. Yang, S.K. Yoon. Hepatology and Gastroenterology, Radiology, The Catholic Medical University, Seoul, Republic of Korea E-mail: mjsong95@gmail.com

Abstract 5738: Expression profiling of microRNA and mRNA on hepatic inflammation in high-fat induced murine model

The inflammation has been identified as a risk factor for cancer and even as a means to prognose/diagnoses cancer at the inception of the inflammatory process. Therefore, it is necessary to discover novel molecules that might play a critical role in the regulation of inflammation, which can be the target of anti-inflammation. Recent reports indicate that microRNAs (miRNAs) have a significant role in the mechanism of inflammation in chronic inflammatory diseases. The goal of this study was to identify and characterize of miRNA in the regulation of inflammatory responses of high-fat induced inflammation mouse model. In this study, we established a mouse model of high-fat-diet-induced inflammation to gain understanding on the biological functions deregulated by aberrant gene expression based on miRNA and mRNA expression profiling analysis. And then we looked for direct miRNA targets by performing pair-wise correlation coefficient analysis on expression levels of mRNAs and by comparing these results with predicted miRNA targets from TargetScan5.1. We used quantitative PCR technology to evaluate the expression of miRNAs and mRNA on liver tissue. Inflammatory foci were observed over 6 months after high-fat induced inflammation mouse. In cDNA microarray analysis, total 2287 genes were differentially expressed between high-fat induced inflammatory group and normal group. Among those genes, the genes related-metabolic pathway were up-regulated at 3 months while those related inflammatory response were up-regulated at late stage of over 6 months in high-fat induced inflammation mouse model. Furthermore, we identified 15 new miRNAs in high-fat induced inflammation model by bioinformatics analysis and further confirmed their expression by stem-loop RT-PCR. GO analysis indicated that many of the identified miRNA targets may function in high-fat induced inflammation model. For three miRNAs (miR-34a, miR-21 and miR-1224), correlated genes were concordant with predicted targets. A gene set enrichment analysis on these genes demonstrated significant enrichment in biological processes related to lipid and glucose metabolism and inflammation. This study represents, to the best of our knowledge, the first integrated analysis of miRNA and mRNA expression in high-fat induced inflammation model. We identified a distinct profile of miRNAs of which expression differed between inflammation and normal, making these miRNAs candidate markers. Supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0014620). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5738. doi:1538-7445.AM2012-5738

220 STEREOTACTIC BODY RADIATION THERAPY ON PORTAL VEIN TUMOR THROMBUS OF HEPATOCELLULAR CARCINOMA

Background and Aims: Lamivudine had comparable antiviral effects both in patients with chronic hepatitis B (CHB) and hepatits B virus (HBV)-related hepatocellular carcinoma (HCC). We aimed to investigate the antiviral and antitumoural effects of entecavir (ETV) in HBV-related HCC patients. Methods: From January 2007 to December 2007, 271 chronically HBV-infected patients were primarily treated with ETV 0.5mg/day for at least 6 months in our institution. Among these, 94 had HCC at the initiation of ETV treatment (HCC group) and 177 did not (non-HCC group). We compared antiviral responses to ETV between the two groups, and also evaluated the influence of ETV on post-treatment outcomes of HCC. Results: At baseline, the HCC group was older, and had higher Child–Pugh score and liver cirrhosis rate than the non-HCC group (all P < 0.05). 33% of the HCC group and 62% of the nonHCC group were positive for Hepatitis B e antigen (HBeAg) (P < 0.05). There were no differences in serum HBV DNA and alanine aminotransferase (ALT) levels between the two groups. The cumulative rates of HBV DNA negativity (<300 copies/ml), ALT normalization, and HBeAg loss at 48 weeks were similar for both groups (86.2%, 85.1% and 43.8%, respectively for the HCC group and 81.4%, 87.6% and 36.4%, respectively for the non-HCC group). After 48 weeks, the HCC group showed significant decreases in mean Child–Pugh and MELD scores, compared with baseline (6.9 vs. 5.8 and 10.1 vs. 8.7, respectively; both P < 0.001). Of the 94 HCC patients, 33 received curative therapies for HCC, simultaneously with ETV: hepatectomy in 9 and radiofrequency ablation in 24. For these subgroup, median recurrence-free survival was 27.9 months in the 21 patients who achieved HBV DNA negativity at week 24, significantly longer than 17.6 months in those who did not (27.9 vs. 17.6 months, P = 0.01), similar to overall survival (P = 0.067): all pretreatment characteristics of patients and tumors did not differ. Conclusions: First-line ETV was comparably efficacious in either CHB patients with or without HCC. ETV treatment improved hepatic function in HCC patients, and early virological response to ETV markedly produced a delay of post-treatment recurrence of HCC.