Hepatitis C virus modulates lipid regulatory factor Angiopoietin-like 3 gene expression by repressing HNF-1 alpha activity

作者：Foka Pelagia^*; Karamichali Eirini; Dalagiorgou Georgia; Serti Elisavet; Doumba Polyxeni P; Pissas George; Kakkanas Athanassios; Kazazi Dorothea; Kochlios Emmanouil; Gaitanou Maria; Koskinas John; Georgopoulou Urania; Mavromara Penelope

来源：Journal of Hepatology, 2014, 60(1): 30-38.

DOI：10.1016/j.jhep.2013.08.016

• Core
• Lipid metabolism
• HCV infection
• Phosphorylation
• Transcriptional regulation

Background & Aims: HCV relies on host lipid metabolism to complete its life cycle and HCV core is crucial to this interaction. Liver secreted ANGPTL-3 is an LXR-and HNF-1 alpha-regulated protein, which plays a key role in lipid metabolism by increasing plasma lipids via inhibition of lipase enzymes. Here we aimed to investigate the modulation of ANGPTL-3 by HCV core and identify the molecular mechanisms involved.
Methods: qRT-PCR and ELISA were used to assess ANGPTL-3 mRNA and protein levels in HCV patients, the JFH-1 infectious system and liver cell lines. Transfections, chromatin immunoprecipitation and immunofluorescence delineated parts of the molecular mechanisms implicated in the core-mediated regulation of ANGPTL-3 gene expression.
Results: ANGPTL-3 gene expression was decreased in HCV-infected patients and the JFH-1 infectious system. mRNA and promoter activity levels were down-regulated by core. The response was lost when an HNF-1 alpha element in ANGPTL-3 promoter was mutated, while loss of HNF-1 alpha DNA binding to this site was recorded in the presence of HCV core. HNF-1 alpha mRNA and protein levels were not altered by core. However, trafficking between nucleus and cytoplasm was observed and then blocked by an inhibitor of the HNF-1 alpha-specific kinase Mirk/Dyrk1B. Transactivation of LXR/RXR signalling could not restore coremediated down-regulation of ANGPTL-3 promoter activity.
Conclusions: ANGPTL-3 is negatively regulated by HCV in vivo and in vitro. HCV core represses ANGPTL-3 expression through loss of HNF-1 alpha binding activity and blockage of LXR/RXR transactivation. The putative ensuing increase in serum lipid clearance and uptake by the liver may sustain HCV virus replication and persistence.

• 出版日期2014-1