Metabolic complications of hepatitis C virus infection

Table 1 The role of major hepatitis C virus proteins in insulin resistance development

HCV core protein	Nonstructural protein 3 (NS3)	Nonstructural protein 5 (NS5)
Activates members of SOCS family; Genotype 1: Activates mTOR and induces phosphorylation of IRS-1; Genotype 3: Upregulates SOCS-7 and downregulates PPARγ	NOX2 activation	Increasing the ROS within the mitochondria
↓ PPARα gene expression in the liver	↑ ROS	Induces ER stress → ↑ protein phosphatase 2A (PP2A)
↓ Assembly of VLDL	Through ROS → Activation of transcriptional factors such as NF-κB and STAT-3 → more advanced stages of chronic hepatitis → oncogenesis	Dephosphorylation and inactivation of Akt
Induces lipogenesis and gluconeogenesis		Stimulates the NF-κB-mediated increase in proinflammatory cytokines
↓ IFN-α production; ↓ IFN-α stimulated genes		Up-regulation of PP2Ac → hypomethylation of STAT-1 → ↑ association of STAT-1 with PIAS1PIAS1 → impairing the transcriptional activation of IFN-stimulated genes
Activation of the pattern-recognition receptor TLR2 → ↑ production of profibrotic factors. i.e. TGF-β, procollagen 1, and MMPs		Stimulates the NF-κB → increase in proinflammatory cytokines (i.e. IL-6, TNF-α)
Activates the PA28γ → ↓ IRS-1 tyrosine phosphorylation and IRS-2 expression and TNF-α promoter activation		Dephosphorylation of PKB/Akt → inhibition of insulin signaling
Induces TNF α → portal or periportal inflammation
Impedes insulin-mediated FoxO1 translocation affecting glucose metabolism

Akt: Protein kinase B; PKB: Protein kinase B; ER: Endoplasmic reticulum; FoxO1: Forkhead box protein O1; IFN-α: Interferon alpha; IL-6: Interleukin-6; IRS-1: Insulin receptor substrate 1; IRS-2: Insulin receptor substrate 2; MMPs: Matrix metalloproteinases; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa light chain; NOX2: NADPH oxidase 2; NS3: Serine protease; NS5: Nonstructural viral proteins NS5A and NS5B; PA28γ: Proteasomal activator; PIAS1: Protein inhibitor of activated STAT 1; PP2Ac: Catalytic subunit of protein phosphatase 2A; ROS: Reactive oxygen species; SOCS: Suppressors of cytokine signaling; SOCS-7: Suppressor Of cytokine signaling 7; STAT-1: Signal transducer and activator of transcription 1; TGF-β: Transforming growth factor beta; TNF-α: Tumor necrosis factor a; TLR2: Toll-like receptor 2; VLDL: Very low density lipoprotein.