Hepatitis C Virus Infection: Molecular Pathways to Steatosis, Insulin Resistance and Oxidative Stress

Clément, Sophie; Pascarella, Stéphanie; Negro, Francesco

doi:10.3390/v1020126

Cited by 46 publications

(37 citation statements)

References 90 publications

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“…AGE formation can be enhanced by oxidative stress or non-oxidative reactions of sugars and their adducts to proteins and lipids. Compared with chronic hepatitis B, chronic hepatitis C is particularly more effective at generating oxidative stress [31]. This notion could partially explain our observation that AGEs were specifically increased in CHC patients.…”

Section: Ages Induce Autophagy In Hscsmentioning

confidence: 84%

Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis

Zhu

Huang

et al. 2015

Acta Diabetol

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Section: Ages Induce Autophagy In Hscsmentioning

confidence: 84%

Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis

Zhu

Huang

et al. 2015

Acta Diabetol

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“…105–107 Therefore, the pathophysiological role of HCV in altered ADME expression cannot be dismissed. Relative mRNA expression of OATP1B1 and OATP2B1 was reduced in the livers of patients with chronic HCV infection, although the mechanistic link between inflammatory cytokines and OATP downregulation is not clear.…”

Section: Introductionmentioning

confidence: 99%

Effect of Liver Disease on Hepatic Transporter Expression and Function

Thakkar

Slizgi

Brouwer

2017

Journal of Pharmaceutical Sciences

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Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. While extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and/or function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and of efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma (HCC), human immunodeficiency virus (HIV) infection, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and primary biliary cirrhosis (PBC) are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition.

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“…Although the exact molecular mechanisms underlying the HCV related liver injury are not fully understood, a growing body of evidence suggests that HCV replication causes accumulation of massive of reactive oxygen species (ROS) and induces oxidative stress in hepatic cells, followed by hepatic cell death, hepatic inflammation and fibrogenesis, a final common pathway for perpetuation of liver damage regardless of the original etiology 2,3 . Viral molecules of HCV could elicit the production of ROS via multiple mechanisms, including alteration of calcium homeostasis 4 , mitochondrial perturbation, induction of NADPH oxidase expression 5 , and activation of endoplasmic reticulum oxidoreductases 6 .…”

Section: Introductionmentioning

confidence: 99%

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

Jiang

Bao

et al. 2014

Gut

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Objective 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. Design GSK3β and Nrf2 signaling pathways were examined in JFH1 hepatitis C virus (HCV) infected Huh 7.5.1 hepatocytes and also in liver biopsy specimens from CHC patients. Results HCV infection elicited prominent Nrf2 antioxidant response in hepatocytes, marked by elevated expression of the Nrf2 dependent molecule heme oxygenase-1 and subsequent protection from apoptotic cell death. Inhibitory phosphorylation of GSK3β seems to be essential and sufficient for HCV induced Nrf2 response. Mechanistically, GSK3β physically associated and interacted with Nrf2 in hepatocytes. In silico analysis revealed that Nrf2 encompasses multiple GSK3β phosphorylation consensus motifs, denoting Nrf2 as a cognate substrate of GSK3β. In the presence of TGFβ1, the HCV induced GSK3β phosphorylation was blunted via a protein phosphatase 1-dependent mechanism and the cytoprotective Nrf2 response drastically impaired. Lithium, a selective inhibitor of GSK3β, counteracted the effects of TGFβ1. In liver biopsy specimens from CHC patients, the expression of phosphorylated GSK3β 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. Conclusions Inhibition of GSK3β exerts hepatoprotection in CHC possibly through its direct regulation of Nrf2 antioxidant response.

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Hepatitis C Virus Infection: Molecular Pathways to Steatosis, Insulin Resistance and Oxidative Stress

Cited by 46 publications

References 90 publications

Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis

Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis

Effect of Liver Disease on Hepatic Transporter Expression and Function

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

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