The replication and infectivity of the lipotropic hepatitis C virus (HCV) are regulated by cellular lipid status. Among differentially expressed microRNAs (miRNAs), we found that miR-27a was preferentially expressed in HCV-infected liver over hepatitis B virus (HBV)-infected liver. Gene expression profiling of Huh-7.5 cells showed that miR-27a regulates lipid metabolism by targeting the lipid synthetic transcription factor RXR␣ and the lipid transporter ATP-binding cassette subfamily A member 1. In addition, miR-27a repressed the expression of many lipid metabolism-related genes, including FASN, SREBP1, SREBP2, PPAR␣, and PPAR␥, as well as ApoA1, ApoB100, and ApoE3, which are essential for the production of infectious viral particles. miR-27a repression increased the cellular lipid content, decreased the buoyant density of HCV particles from 1.13 to 1.08 g/cm 3 , and increased viral replication and infectivity. miR-27a overexpression substantially decreased viral infectivity. Furthermore, miR-27a enhanced in vitro interferon (IFN) signaling, and patients who expressed high levels of miR-27a in the liver showed a more favorable response to pegylated IFN and ribavirin combination therapy. Interestingly, the expression of miR-27a was upregulated by HCV infection and lipid overload through the adipocyte differentiation transcription factor C/EBP␣. In turn, upregulated miR27a repressed HCV infection and lipid storage in cells. Thus, this negative feedback mechanism might contribute to the maintenance of a low viral load and would be beneficial to the virus by allowing it to escape host immune surveillance and establish a persistent chronic HCV infection. MicroRNA (miRNA) is a small, endogenous, single-stranded, noncoding RNA consisting of 20 to 25 bases that regulates gene expression. It plays an important role in various biological processes, including organ development, differentiation, and cellular death and proliferation, and is also involved in infection and diseases such as cancer (1).Previously, we examined miRNA expression in hepatocellular carcinoma (HCC) and noncancerous background liver tissue infected with hepatitis B virus (HBV) and HCV (2). We showed that some miRNAs were differentially expressed according to HBV or HCV infection but not according to the presence of HCC. These infection-specific miRNAs were believed to regulate HBV or HCV replication; however, their functional role has not been elucidated.HCV is described as a lipotropic virus because of its association with serum lipoprotein (3-5). It utilizes the low-density lipoprotein (LDL) receptor for cellular entry (6-8) and forms replication complexes on lipid rafts (9). The HCV core protein surrounds and binds lipid droplets (LDs) and nonstructural proteins on the endoplasmic reticulum (ER) membrane, which is essential for particle formation (10). Moreover, HCV cellular secretion is linked to very LDL (VLDL) secretion (11). In liver tissue histology, steatosis is often observed in chronic hepatitis C (CH-C) and is closely related to resistance ...
Background & aimsThe modest consumption of alcohol has been reported to decrease the incidence of fatty liver or prevalence of steatohepatitis. In this study, we investigated the effect of light alcohol consumption on liver function and gene expression in patients with non-alcoholic fatty liver disease (NAFLD).MethodsThe study group was formed of 178 patients diagnosed with non-alcoholic fatty liver disease, subclassified into two groups for analysis based on the daily alcohol consumption: non-alcohol group and light alcohol consumer group (≤20 g of ethanol/day). Clinical characteristics, liver histological features, gene expression, comprehensively analyzed using microarrays (BRB-Array tools), and molecular network were evaluated and compared between the two groups.ResultsNo significant differences in steatosis or inflammation score were noted among the groups. However, the ballooning and fibrosis scores were significantly lower in the light alcohol consumer group than in the non-alcohol group. Gene expression analysis revealed a marked inhibition of the pathways involved in the immune response in the light alcohol group compared to that in the non-alcohol group.ConclusionsLight alcohol consumption might suppress activity of non-alcoholic steatohepatitis by reducing gene expression levels involved in the immune response. This inhibition in gene expression was associated with a lowering of liver fibrosis and hepatocellular injury.
Pretreatment up-regulation of hepatic interferon (IFN)-stimulated genes (ISGs) has a stronger association with the treatment-resistant interleukin (IL)28B minor genotype (MI; TG/GG at rs8099917) than with the treatment-sensitive IL28B major genotype (MA; TT at rs8099917). We compared the expression of ISGs in the liver and blood of 146 patients with chronic hepatitis C who received pegylated IFN and ribavirin combination therapy. Gene expression profiles in the liver and blood of 85 patients were analyzed using an Affymetrix GeneChip (Affymetrix, Santa Clara, CA). ISG expression was correlated between the liver and blood of the MA patients, whereas no correlation was observed in the MI patients. This loss of correlation was the result of the impaired infiltration of immune cells into the liver lobules of MI patients, as demonstrated by regional gene expression analysis in liver lobules and portal areas using laser capture microdissection and immunohistochemical staining. Despite having lower levels of immune cells, hepatic ISGs were up-regulated in the liver of MI patients and they were found to be regulated by multiple factors, namely, IL28A/B, IFN-k4, and wingless-related MMTV integration site 5A (WNT5A). Interestingly, WNT5A induced the expression of ISGs, but also increased hepatitis C virus replication by inducing the expression of the stress granule protein, GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1), in the Huh-7 cell line. In the liver, the expression of WNT5A and its receptor, frizzled family receptor 5, was significantly correlated with G3BP1. Conclusions: Immune cells were lost and induced the expression of other inflammatory mediators, such as WNT5A, in the liver of IL28B minor genotype patients. This might be related to the high level of hepatic ISG expression in these patients and the treatment-resistant phenotype of the IL28B minor genotype. (HEPATOLOGY 2014;59:828-838)
BackgroundPortal vein thrombosis (PVT) is a common complication of cirrhosis. However, in patients with PVT and cirrhosis, there is no clear evidence supporting effective treatment modalities. In this study, we examined the effectiveness and safety of anticoagulation therapy using danaparoid sodium for PVT in patients with cirrhosis.MethodsThis retrospective study assessed 52 cirrhotic patients with PVT treated with danaparoid sodium for 2 weeks between November 2008 and September 2018. The primary outcome measure was the post-treatment status of PVT assessed by reduction in thrombus volume and safety of the therapeutic intervention. PVT status was evaluated with contrast-enhanced computed tomography (CECT). All patients received 1250 units of danaparoid sodium twice daily by intravenous injection for 14 days. Patients on antithrombin III (AT-III) combination therapy were additionally administered 1500 units of AT-III on days 1–5 and days 8–12. Effectiveness was evaluated by CECT from between days 13 and 18. The secondary outcome measure was the prognosis of PVT.ResultsAll patients showed reduction in PVT volume without complications. Return of plasma AT-III level to > 70% during the treatment period contributes to ≥75% reduction of PVT volume. The prognosis in PVT patients depends on hepatic reserve capacity. When limited to Child-Pugh B and C liver cirrhosis patients, a ≥ 75% reduction of PVT volume improved the prognosis.ConclusionsDanaparoid sodium-based anticoagulation therapy was effective and safe for PVT in patients with cirrhosis. Return of plasma AT-III level to the normal range during the treatment period contributes to reduction of PVT volume. A reduction of ≥75% in PVT volume may improve the prognosis of Child-Pugh B and C decompensated cirrhosis patients with PVT.
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