[65] Here, we discuss the mechanisms by which hepatic iron accumulates in chronic hepatitis C, focusing on the relationship between HCV-induced ROS production and iron metabolic disorder. Systemic iron homeostasis is mainly regulated both by intestinal absorption and macrophage recycling of iron from hemoglobin because there is no efficient pathway

for iron excretion.[69] Hepcidin, which was originally isolated from human serum and urine as a peptide with antimicrobial activity,[70] is a hormone exclusively synthesized in the liver and a soluble regulator that acts to attenuate both intestinal iron absorption MK-1775 in vitro and iron release from reticuloendothelial macrophages.[71] Hepatic mRNA levels[72] and the 25 amino acid bioactive hepcidin levels in serum[73] are lower in chronic hepatitis C than in chronic hepatitis B or controls, despite a significant correlation between hepcidin and serum ferritin or the histological iron score. Thus, the relatively decreased synthesis of hepcidin in chronic hepatitis C contrasts with the absolute deficit or lack of hepcidin synthesis observed in hereditary hemochromatosis. The detailed mechanisms underlying the transcriptional regulation of hepcidin are discussed elsewhere.

Interestingly, alcohol metabolism-mediated ROS were shown to suppress hepcidin transcription via CCAAT/enhancer-binding protein α (C/EBPα).[74] In parallel with these results, we found that hepcidin promoter

activity and the DNA binding activity of C/EBPα were downregulated concomitant with increased expression of C/EBP homology protein (CHOP), an inhibitor PD-1/PD-L1 inhibitor drugs of C/EBP DNA binding activity, and with increased levels of mitochondrial ROS in transgenic mice expressing the HCV polyprotein.[75] There are several lines of evidence indicating that ROS upregulate the expression of CHOP.[76] In agreement with our observation, an in vitro study using hepatoma cells showed that HCV-induced ROS inhibited the binding activity of C/EBPα and signal transduction and activator of transcription 3 to the hepcidin promoter in addition to stabilization of hypoxia-inducible factor through increased histone deacetylase activity.[77] Thus, HCV core-induced mitochondrial ROS accumulate hepatic iron through the inhibition of hepcidin transcription 上海皓元 (Fig. 3). IN THE PRESENT review we discussed how HCV interacts with mitochondria and how subsequently occurring mitochondrial ROS production contributes to the pathophysiology of HCV-related chronic liver diseases. The mitochondrion is the key organelle that determines the cellular response to various kinds of biological stress. Therefore, it may not be surprising that HCV-induced alterations of mitochondrial functions have a critical impact on disease progression towards hepatocarcinogenesis by creating an oxidatively stressed liver microenvironment through mitochondrial ROS production.