Copyright ©The Author(s) 2021.
World J Gastroenterol. Apr 7, 2021; 27(13): 1267-1282
Published online Apr 7, 2021. doi: 10.3748/wjg.v27.i13.1267
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 PPARγNOX2 activationIncreasing the ROS within the mitochondria
↓ PPARα gene expression in the liver↑ ROSInduces ER stress → ↑ protein phosphatase 2A (PP2A)
↓ Assembly of VLDLThrough ROS → Activation of transcriptional factors such as NF-κB and STAT-3 → more advanced stages of chronic hepatitis → oncogenesisDephosphorylation and inactivation of Akt
Induces lipogenesis and gluconeogenesisStimulates the NF-κB-mediated increase in proinflammatory cytokines
↓ IFN-α production; ↓ IFN-α stimulated genesUp-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 MMPsStimulates 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 activationDephosphorylation of PKB/Akt → inhibition of insulin signaling
Induces TNF α → portal or periportal inflammation
Impedes insulin-mediated FoxO1 translocation affecting glucose metabolism