Functional involvement of endothelial lipase in hepatitis B virus infection.

BACKGROUND: HBV infection causes chronic liver disease and leads to the development of HCC. To identify host factors that support the HBV life cycle, we previously established the HC1 cell line that maintains HBV infection and identified host genes required for HBV persistence. METHODS: The present study focused on endothelial lipase (LIPG), which binds to heparan sulfate proteoglycans (HSPGs) in the cell membrane. RESULTS: We found HBV infection was impaired in humanized liver chimeric mouse-derived hepatocytes that were transduced with lentivirus expressing short hairpin RNA against LIPG. Long-term suppression of LIPG combined with entecavir further suppressed HBV replication. LIPG was shown to be involved in HBV attachment to the cell surface by using 2 sodium taurocholate cotransporting peptide (NTCP)-expressing cell lines, and the direct interaction of LIPG and HBV large surface protein was revealed. Heparin and heparinase almost completely suppressed the LIPG-induced increase of HBV attachment, indicating that LIPG accelerated HBV attachment to HSPGs followed by HBV entry through NTCP. Surprisingly, the attachment of a fluorescently labeled NTCP-binding preS1 probe to NTCP-expressing cells was not impaired by heparin, suggesting the HSPG-independent attachment of the preS1 probe to NTCP. Interestingly, attachment of the preS1 probe was severely impaired in LIPG knockdown or knockout cells. Inhibitors of the lipase activity of LIPG similarly impaired the attachment of the preS1 probe to NTCP-expressing cells. CONCLUSIONS: LIPG participates in HBV infection by upregulating HBV attachment to the cell membrane by means of 2 possible mechanisms: increasing HBV attachment to HSPGs or facilitating HSPG-dependent or HSPG-independent HBV attachment to NTCP by its lipase activity.

Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET.

Retinoic acid-inducible gene (RIG)-I is an essential innate immune sensor that recognises pathogen RNAs and induces interferon (IFN) production. However, little is known about how host proteins regulate RIG-I activation. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2), a hepatokine and ligand of the MET receptor tyrosine kinase is an antiviral regulator that promotes the RIG-I-mediated innate immune response. Upon binding to MET, LECT2 induces the recruitment of the phosphatase PTP4A1 to MET and facilitates the dissociation and dephosphorylation of phosphorylated SHP2 from MET, thereby protecting RIG-I from SHP2/c-Cbl-mediated degradation. In vivo, LECT2 overexpression enhances RIG-I-dependent IFN production and inhibits lymphocytic choriomeningitis virus (LCMV) replication in the liver, whereas these changes are reversed in LECT2 knockout mice. Forced suppression of MET abolishes IFN production and antiviral activity in vitro and in vivo. Interestingly, hepatocyte growth factor (HGF), an original MET ligand, inhibits LECT2-mediated anti-viral signalling; conversely, LECT2-MET signalling competes with HGF-MET signalling. Our findings reveal previously unrecognized crosstalk between MET-mediated proliferation and innate immunity and suggest that targeting LECT2 may have therapeutic value in infectious diseases and cancer.

MicroRNA-10a Impairs Liver Metabolism in Hepatitis C Virus-Related Cirrhosis Through Deregulation of the Circadian Clock Gene Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocator-Like 1.

The circadian rhythm of the liver plays an important role in maintaining its metabolic homeostasis. We performed comprehensive expression analysis of microRNAs (miRNAs) using TaqMan polymerase chain reaction of liver biopsy tissues to identify the miRNAs that are significantly up-regulated in advanced chronic hepatitis C (CHC). We found miR-10a regulated various liver metabolism genes and was markedly up-regulated by hepatitis C virus infection and poor nutritional conditions. The expression of miR-10a was rhythmic and down-regulated the expression of the circadian rhythm gene brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal1) by directly suppressing the expression of RA receptor-related orphan receptor alpha (RORA). Overexpression of miR-10a in hepatocytes blunted circadian rhythm of Bmal1 and inhibited the expression of lipid synthesis genes (sterol regulatory element binding protein [SREBP]1, fatty acid synthase [FASN], and SREBP2), gluconeogenesis (peroxisome proliferator-activated receptor gamma coactivator 1 alpha [PGC1α]), protein synthesis (mammalian target of rapamycin [mTOR] and ribosomal protein S6 kinase [S6K]) and bile acid synthesis (liver receptor homolog 1 [LRH1]). The expression of Bmal1 was significantly correlated with the expression of mitochondrial biogenesis-related genes and reduced Bmal1 was associated with increased serum alanine aminotransferase levels and progression of liver fibrosis in CHC. Thus, impaired circadian rhythm expression of Bmal1 by miR-10a disturbs metabolic adaptations, leading to liver damage, and is closely associated with the exacerbation of abnormal liver metabolism in patients with advanced CHC. In patients with hepatitis C-related liver cirrhosis, liver tissue miR-10a levels were significantly associated with hepatic reserve, fibrosis markers, esophageal varix complications, and hepatitis C-related hepatocellular carcinoma recurrence. Conclusion: MiRNA-10a is involved in abnormal liver metabolism in cirrhotic liver through down-regulation of the expression of the circadian rhythm gene Bmal1. Therefore, miR-10a is a possible useful biomarker for estimating the prognosis of liver cirrhosis.