Τίτλος:
Hepatitis C virus modulates lipid regulatory factor Angiopoietin-like 3
gene expression by repressing HNF-1 alpha activity
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. (C) 2013
European Association for the Study of the Liver. Published by Elsevier
B.V. All rights reserved.
Συγγραφείς:
Foka, Pelagia
Karamichali, Eirini
Dalagiorgou, Georgia and
Serti, Elisavet
Doumba, Polyxeni P.
Pissas, George
Kakkanas,
Athanassios
Kazazi, Dorothea
Kochlios, Emmanouil
Gaitanou,
Maria
Koskinas, John
Georgopoulou, Urania
Mavromara,
Penelope
Περιοδικό:
WORLD JOURNAL OF HEPATOLOGY
Εκδότης:
ELSEVIER SCIENCE BV
Λέξεις-κλειδιά:
Core; Lipid metabolism; HCV infection; Phosphorylation; Transcriptional
regulation
DOI:
10.1016/j.jhep.2013.08.016
