Expression of Biliverdin Reductase A in Peripheral Blood Leukocytes Is Associated with Treatment Response in HCV-Infected Patients

Abstract

Background and AimsHepatitis C virus (HCV) infection is associated with systemic oxidative stress. Since the heme catabolic pathway plays an important role in antioxidant protection, we attempted to assess the gene expression of key enzymes of heme catabolism, heme oxygenase 1 (HMOX1), heme oxygenase 2 (HMOX2), and biliverdin reductase A (BLVRA) in the liver and peripheral blood leukocytes (PBL) of patients chronically infected with HCV.MethodsGene expressions (HMOX1, HMOX2, BLVRA) and HCV RNA were analyzed in PBL of HCV treatment naïve patients (n = 58) and controls (n = 55), with a subset of HCV patients having data on hepatic gene expression (n = 35). Based upon the therapeutic outcome, HCV patients were classified as either responders (n = 38) or treatment-failure patients (n = 20). Blood samples in HCV patients were collected at day 0, and week 12, 24, 36, and 48 after the initiation of standard antiviral therapy.ResultsCompared to the controls, substantially increased BLVRA expression was detected in PBL (p<0.001) of therapeutically naïve HCV patients. mRNA levels of BLVRA in PBL closely correlated with those in liver tissue (r2 = 0.347,p = 0.03). A marked difference in BLVRA expression in PBL between the sustained responders and patients with treatment failure was detected at week 0 and during the follow-up (p<0.001). Multivariate analysis revealed that BLVRA basal expression in PBL was an independent predictor for sustained virological response (OR 15; 95% CI 1.05–214.2; P = 0.046). HMOX1/2 expression did not have any effect on the treatment outcome.ConclusionOur results suggest that patients with chronic HCV infection significantly upregulate BLVRA expression in PBL. The lack of BLVRA overexpression is associated with non-responsiveness to standard antiviral therapy; whereas, HMOX1/2 does not seem to have any predictive potential.

Rethinking the immune properties of bilirubin in viral hepatitis: from bench to bedside

“…Supporting the putative modulation of cellular immune responses during HAV infection, CBR levels >0.3 to <2 mg dl −1 result in the secretion of TGF‐β and increased STAT‐1 and STAT‐5 phosphorylation, whereas CBR levels >2 mg dl −1 correlate with a reduction in the proportion of peripheral blood lymphoid cells positive for STAT‐5 phosphorylation and increased levels of IL‐6 29 . Interestingly, it is known that STAT‐5 acts as an important mediator of Foxp3 expression and Treg function and that the release of TGF‐β in the serum during acute viral infection inhibits antigen‐specific T‐cell activation and proliferation as a result of modulating Treg cell activity 45 . Thus, it is tempting to speculate that the global immune response against HAV may be influenced by the CBR levels in serum.…”

“…Decreased levels of the HCV NS3/4A protease correlate with lower viral replication in in vitro infected hepatocytes because of triggering of the antiviral interferon response 52 , 53 . In addition, BVR upregulation has been observed in chronically HCV‐infected patients with a sustained response to treatment relative to nonresponding patients 45 . Furthermore, the induction of HO‐1 in HCV infection has been shown to decrease viral replication, as well as protect against oxidative damage 54 .…”

“…29 Interestingly, it is known that STAT-5 acts as an important mediator of Foxp3 expression and Treg function and that the release of TGF-β in the serum during acute viral infection inhibits antigen-specific T-cell activation and proliferation as a result of modulating Treg cell activity. 45 Thus, it is tempting to speculate that the global immune response against HAV may be influenced by the CBR levels in serum. During HAV infection, low levels of CBR (40.3-2 mg dl − 1 ) may result in Treg cell activation, whereas high levels of CBR (42 mg dl − 1 ) could induce Treg cell inactivation.…”

“…52,53 In addition, BVR upregulation has been observed in chronically HCV-infected patients with a sustained response to treatment relative to nonresponding patients. 45 Furthermore, the induction of HO-1 in HCV infection has been shown to decrease viral replication, as well as protect against oxidative damage. 54 Taken together, changes in the activity or levels of heme-related enzymes and metabolites may be related to a protective role against hepatocellular injury during HCV-mediated viral hepatitis and could represent potential targets for novel antiviral approaches based on this metabolic pathway.…”

<p>Biliverdin Reductase A (BLVRA) Promotes Colorectal Cancer Cell Progression by Activating the Wnt/β-Catenin Signaling Pathway</p>

“…[5][6][7][8] Overexpression of BLVRA has been reported in many diseases, including cancers. The level of BLVRA is rather high in many cancers, including liver cancer, 6,9 lung cancer, 7 breast cancer, 10 skin cancer, 11 and esophageal cancer. 12 However, the role of BLVRA in CRC has not yet been fully elucidated.…”