Orexin A ameliorates HBV X protein-induced cytotoxicity and inflammatory response in human hepatocytes.
ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY(2019)
摘要
Hepatitis B virus is one of the main causes of hepatitis and hepatocellular carcinoma (HCC). Hepatitis B virus-encoded X protein (HBx) has been shown to be involved in many aspects of the pathogenicity of liver diseases. Orexin A is a small peptide produced in the hippocampus. Orexin A and its receptor have become important therapeutic targets for certain metabolic disorders. In this study, we show that orexin A has a protective role against HBx-induced cytotoxicity and inflammation in hepatocytes. The ectopic expression of HBx in hepatocytes reduces orexin A receptor 1 (OX1R) expression. When orexin A is added to the cells, it mitigates HBx-induced oxidative stress indicator 4-hydroxynonenal (4-HNE) and reactive oxygen species (ROS) as well the NADPH subunit NADPH oxidase 4 (NOX-4). Orexin A also ameliorates HBx-mediated mitochondrial membrane potential and adenosine triphosphate (ATP) reduction. Moreover, orexin A significantly inhibits HBx-induced production of pro-inflammatory cytokines including interleukin 8 (IL-8), tumour necrosis factor alpha (TNF-alpha) and chemokine ligand 2 (CXCL2). The presence of orexin A ameliorates HBx-induced lactate dehydrogenase (LDH) release, indicating that it could protect hepatocytes from cytotoxicity. Mechanistically, we found that orexin A suppresses c-Jun N-terminal kinase (JNK) phosphorylation, accumulation of nuclear factor-B (NF-kappa B) protein p65 in nuclei, and NF-kappa B promoter activity, suggesting that orexin A suppresses JNK and NF-kappa B pathway activation. In conclusion, our study demonstrates that orexin A peptide possesses a protective role against HBx-mediated cytotoxicity and inflammation in hepatocytes.
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关键词
HBV protein x (HBx),orexin A,hepatocytes,cytotoxicity,inflammation,JNK,NF-kappa B
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