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Therapeutic targeting of GSK3? enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C.

ABSTRACT: Impaired adaptive response to oxidative injuries is a fundamental mechanism central to the pathogenesis of chronic hepatitis C (CHC). Glycogen synthase kinase (GSK) 3? is an indispensable regulator of the oxidative stress response. However, the exact role of GSK3? in CHC is uncertain and was examined.GSK3? and Nrf2 signalling pathways were examined in JFH1 HCV infected Huh7.5.1 hepatocytes, and also in liver biopsy specimens from CHC patients.HCV infection elicited prominent Nrf2 antioxidant response in hepatocytes, marked by elevated expression of the Nrf2-dependent molecule haem oxygenase-1 and subsequent protection from apoptotic cell death. Inhibitory phosphorylation of GSK3? seems to be essential and sufficient for HCV-induced Nrf2 response. Mechanistically, GSK3? associated and physically interacted with Nrf2 in hepatocytes. In silico analysis revealed that Nrf2 encompasses multiple GSK3? phosphorylation consensus motifs, denoting Nrf2 as a cognate substrate of GSK3?. In the presence of TGF?1, the HCV-induced GSK3? phosphorylation was blunted via a protein phosphatase 1-dependent mechanism and the cytoprotective Nrf2 response drastically impaired. This effect was counteracted by lithium, a selective inhibitor of GSK3?. In liver biopsy specimens from CHC patients, the expression of phosphorylated GSK3? positively correlated with Nrf2 expression and was inversely associated with the degree of liver injury. Moreover, CHC patients who received long-term lithium carbonate therapy primarily for concomitant psychiatric disorders exhibited much less liver injury, associated with enhanced hepatic expression of Nrf2.Inhibition of GSK3? exerts hepatoprotection in CHC possibly through its direct regulation of Nrf2 antioxidant response.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC4263291 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Therapeutic targeting of GSK3β enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C.

Jiang Yongfang Y Bao Hui H Ge Yan Y Tang Wei W Cheng Du D Luo Kaizhong K Gong Guozhong G Gong Rujun R

Gut 20140508 1

<h4>Objective</h4>Impaired adaptive response to oxidative injuries is a fundamental mechanism central to the pathogenesis of chronic hepatitis C (CHC). Glycogen synthase kinase (GSK) 3β is an indispensable regulator of the oxidative stress response. However, the exact role of GSK3β in CHC is uncertain and was examined.<h4>Design</h4>GSK3β and Nrf2 signalling pathways were examined in JFH1 HCV infected Huh7.5.1 hepatocytes, and also in liver biopsy specimens from CHC patients.<h4>Results</h4>HCV ...[more]

PMID: 24811996

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Project description:Abnormally increased resorption contributes to bone degenerative diseases such as Paget's disease of bone (PDB) through unclear mechanisms. Recently, the optineurin (OPTN) gene has been implicated in PDB, and global OPTN knockout mice (Optn-/-) were shown to exhibit increased formation of osteoclasts (osteoclastogenesis). Growing evidence, including our own, has demonstrated that intracellular reactive oxygen species (ROS) stimulated by receptor activator of nuclear factor kappa-B ligand (RANKL) can act as signaling molecules to promote osteoclastogenesis. Here, we report that OPTN interacts with nuclear factor erythroid-derived factor 2-related factor 2 (NRF2), the master regulator of the antioxidant response, defining a pathway through which RANKL-induced ROS could be regulated for osteoclastogenesis. In this study, monocytes from Optn-/- and wild-type (Optn+/+) mice were utilized to differentiate into osteoclasts, and both qRT-PCR and tartrate-resistant acid phosphatase (TRAP) staining showed that the Optn-/- monocytes exhibited enhanced osteoclastogenesis compared to the Optn+/+ cells. CellROX® staining, qRT-PCR, and Western blotting indicated that OPTN deficiency reduced the basal expression of Nrf2, inhibited the expression of NRF2-responsive antioxidants, and increased basal and RANKL-induced intracellular ROS levels, leading to enhanced osteoclastogenesis. Coimmunoprecipitation (co-IP) showed direct interaction, and immunofluorescence staining showed perinuclear colocalization of the OPTN-NRF2 granular structures during differentiation. Finally, curcumin and the other NRF2 activators attenuated the hyperactive osteoclastogenesis induced by OPTN deficiency. Collectively, our findings reveal a novel OPTN-mediated mechanism for regulating the NRF2-mediated antioxidant response in osteoclasts and extend the therapeutic potential of OPTN in the aging process resulting from ROS-triggered oxidative stress, which is associated with PDB and many other degenerative diseases.

Dataset Information

Therapeutic targeting of GSK3? enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C.

Publications

Therapeutic targeting of GSK3β enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C.

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