Naringenin improve hepatitis C virus infection induced insulin resistance by increase PTEN expression via p53-dependent manner

Hepatitis C virus (HCV) infection may finally lead to hepatocellular carcinoma (HCC), and also associated with insulin resistance (IR). Naringenin (NGEN), a flavonoid found in grapefruit, has anti-virus, anti-inflammation and insulin sensitization effects. In the present study we examined the effects of NGEN on HCV core protein (HCVCP) infection induced IR and investigated the mechanism involved. We found that NGEN ameliorated IR and glucose tolerance in HCVCP infected mice by increase the phosphorylation of Akt at both Ser473 and Thr308 site, and also inhibited the inflammation cytokine production and T-cell immune response. Similar to the in vivo results, NGEN also improved the insulin response and showed anti-inflammation effect in HCVCP infected Huh-7.5.1 cells. In addition, NGEN up-regulated the phosphatase and tensin homolog deleted on chromosome ten (PTEN) both in protein and mRNA levels. Furthermore, overexpress of PTEN abolished the HCVCP-stimulated IR and decreased the inflammation cytokine release. NGEN also blocked the interaction between HCVCP and p53, upregulated the endogenous p21/waf1 expression which indiacting the activation of p53. The p53 wild type could upregulate NGEN-stimulated PTEN expression while R273H mut-p53 showed no similar function. Our data reveals that NGEN increases insulin sensitivity in HCVCP infected liver by up-regulating PTEN in p53-dependent manner.