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Title: The dysregulation of lipid metabolism caused by hepatitis C virus
Author: Burch, Charles
ISNI:       0000 0004 7657 8933
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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The life cycle of HCV involves a dysregulation in host lipid metabolism that may precede metabolic complications such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), and hepatic steatosis which are often associated with chronic infection. Thioredoxin-Interacting Protein (TXNIP), a host factor that is induced by oxidative stress, and associated with disturbances in host lipid and glucose metabolism, has been reported to be overexpressed during HCV infection where its siRNA-mediated knockdown resulted in a significant impairment of virus replication. This study investigated the mechanisms by which HCV may bring about the overexpression of TXNIP by examining the unfolded protein response (UPR) and mitochondrial dysfunction in HCV gt2a infection models. These pathways were tested in HCV SGR- and JFH-1 infected Huh7 cells by targeting inositol-requiring enzyme 1α (IRE-1α) activity and mitochondrial voltage-dependent anion channel (VDAC) oscillation, and the effects on TXNIP expression, lipid metabolism, and virus replication were measured. The data from this work indicate that the UPR is more relevant to HCV SGR replication, whilst ameliorating mitochondrial dysfunction appears to restore glucose metabolism, downregulate lipogenic gene transcription, inhibit lipid droplet (LD) biogenesis, and reduce JFH-1 RNA replication.
Supervisor: McGarvey, Michael Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral