Mechanism(s) of hepatitis C virus induced liver injury

Wilson, Garrick Kenardo (2012). Mechanism(s) of hepatitis C virus induced liver injury. University of Birmingham. Ph.D.

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Abstract

Hepatitis C virus (HCV) infects hepatocytes of the liver causing progressive liver disease including; fibrosis, cirrhosis and hepatocellular carcinoma. However, the precise mechanism(s) underlying HCV induced liver injury are poorly understood. Hepatocytes are highly polarized with distinct apical and basolateral membranes separated by tight junctions that maintain a normal liver physiology. We studied the role of HCV infection in driving hepatic injury. Our studies show that HCV infection induces hepatocellular reprogramming via hypoxia inducible factor-1α (HIF-1α) stabilization and increased glucocorticoid receptor (GR) signaling. HIF-1α stabilization promoted epithelial to mesenchymal transition accompanied by reduced polarity and cell adhesion. Whereas GR signaling increased cholesterol synthesis and altered HCV receptor expression. Alterations in hepatocellular biology induced a cellular state conducive for virus entry and replication.

Consequently, cells de-differentiate to acquire a malignant phenotype via HIF-1α target genes including vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF). In addition, GR transcription induced by glucocorticoid treatment or HCV infection enhanced virus uptake, highlighting the caveat for glucocorticoid immunosuppression post liver transplantation. Importantly, HIF-1α inhibitors and GR antagonist reversed the effects of both transcription factors on virus infection and hepatocellular biology. These findings suggest that HCV potentiate liver injury via indirect mechanisms.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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