Background: Patients with chronic hepatitis C (CHC) are more likely to develop type 2 diabetes (T2D), and CHC patients with T2D are at a higher risk for worse outcomes from hepatitis C virus (HCV) infection, progression to fibrosis, and the development of hepatocellular carcinoma. Previously, we reported that selenoprotein P (SeP), a liver-specific secretory protein, causes insulin resistance. In this study, we explored the relationship between HCV infection and SeP.
Methods: SeP knockdown (KD) cells were prepared using lentivirus system. The cells were then transfected with HCV-RNA or polyinosinic-polycytidylic acid (PolyI:C), and immune responses were evaluated by RTD-PCR or western blotting. SeP serum levels were measured in 290 CHC patients who were treated with direct-acting antivirals (DAAs).
Results: HCV infection activated the SeP promoter by increasing CEBPα levels (a transcription factor). SeP KD substantially increased the HCV-RNA- or PolyI:C-stimulated production of interferon (IFN)-β, and repressed HCV replication in KH cells (hepatoma cells with preserved type I IFN signaling, established in-house). However, this effect was lost in RIG-I-null Huh-7.5 cells. Screening innate immune genes using siRNAs revealed that the RIG-I/MAVS/IRF3 pathway may be involved in SeP KD-mediated immune stimulation. Interestingly, SeP mRNA bound directly to RIG-I and inhibited RIG-I-mediated type I IFN responses. The selenocysteine insertion sequences in the 3′ and 5′ untranslated regions of SeP mRNA were indispensable for the inhibition of RIG-I activity, suggesting that the secondary or tertiary structure of SeP mRNA might be important for this interaction. Among 290 CHC patients, high serum SeP was significantly associated with DAA failure.
Conclusions: HCV infection increases SeP, which causes insulin resistance. SeP mRNA binds RIG-I protein and inhibits the RIG-I-mediated type I IFN response, which might be related to DAA failure. These results show that SeP plays pivotal roles in glucose metabolism and anti-viral innate immunity in the liver.