The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms

Abstract

Both molecular and clinical evidence support a link between HCV infection and insulin resistance. We examined the in vitro interaction between the HCV core protein of genotypes 3a and 1b with the insulin-signaling pathway. We measured the expression levels of insulin receptor substrate 1 (IRS-1), IRS-2, and other factors involved in the insulin signal pathway in a human hepatoma cell line (Huh-7) transiently expressing the HCV core protein of genotypes 3a or 1b by molecular biology and biochemical techniques. The IRS-1 (but not IRS-2) protein level was significantly reduced in Huh-7 expressing the core protein of both genotypes 3a and 1b, as compared to cells transfected with the empty vector. However, while the core protein of genotype 3a promoted IRS-1 degradation through the downregulation of peroxisome proliferator-activated receptor ␥ (PPAR␥) and by upregulating the suppressor of cytokine signal 7 (SOCS-7), the core protein of genotype 1b activated the mammalian target of rapamycin (mTOR). We confirmed these findings by using agonists for PPAR␥ (rosiglitazone) or short interfering RNAs for SOCS-7. Conclusion: Despite the small sequence divergence of the HCV core proteins of genotypes 3a and 1b, the 2 proteins appear to interfere with the insulin signaling pathway using genotype-specific mechanisms.

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

“…13 In keeping with our observation of an association between HCV RNA and low cholesterol in HCV G3, intrahepatic G3 HCV RNA has also been shown to correlate directly with other metabolic consequences of infection such as steatosis, further supporting a possible direct viral pathogenic effect. 31 Oxidative stress in the endoplasmic reticulum has been linked to lipogenesis 32 and HCV infection.…”

“…13 Direct viral perturbation of cholesterol biosynthetic pathways and their regulation is suggested from experimental in vitro and animal models. [14][15][16][17][18] HCV-mediated oxidative stress has been suggested as a possible causative mechanism leading to both HCV-associated hepatic steatosis and IR, and has also been linked to cholesterol regulation.…”

Homeostasis model assessment of insulin resistance does not seem to predict response to telaprevir in chronic hepatitis C in the REALIZE trial

“…5,6,29 However, although SOCS-3 has been reportedly elevated in the liver of chronic hepatitis C patients with IR, 7 its role in reducing the response to therapy has been challenged by experimental 30 and clinical data. 31 A second hypothesis is based on data suggesting that high concentrations of insulin directly inhibit interferon alpha signaling, independently of SOCS-3.…”

“…Plasma HCV RNA was measured using the COBAS TaqMan assay, v. 2.0 (Roche, Switzerland; lower limit of quantification 25 IU/mL and lower limit of detection 10 IU/mL) at screening, baseline, day 3, during weeks 1, 2, 4, 5,6,8,10,12,14,16,20,24,36, and 48, at early discontinuation, at follow-up visits 4, 12, and 24 weeks after end of treatment and at week 72, even in patients who discontinued early. SVR was defined as having undetectable (<25 IU/mL undetectable) HCV RNA at 24 weeks after the last planned dose of study medication.…”

“…2,3 Proposed mechanisms for HCV-related IR and diabetes mellitus include direct hepatic effects [4][5][6] and potential contributions from extrahepatic organs. 7,8 In HCV-infected patients, IR appears to influence disease progression and response to treatment with peginterferon alpha and ribavirin.…”