PKC signaling in oxidative hepatic damage

Nitti, Mariapaola; Pronzato, Maria Adelaide; Marinari, Umberto M.; Domenicotti, Cinzia

doi:10.1016/j.mam.2007.09.001

Cited by 43 publications

(30 citation statements)

References 45 publications

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“…Clearly, this result could be explained by increases in HO-1, GPX3 and NCF2 and decreases in GCS and 3αHSD expression levels. We also found upregulation of other oxidative stress–induced genes, such as Prkcd [41] and Cybb (also named Nox2, a phagocyte NADPH oxidase; for further details see Text S1). CYBB generates ROS in a highly regulated fashion under physiological conditions, but in disease states, its deregulation contributes to oxidative stress and subsequent tissue damage [42].…”

Section: Discussionmentioning

confidence: 73%

Alteration of Gene Expression Profile in Niemann-Pick Type C Mice Correlates with Tissue Damage and Oxidative Stress

et al. 2011

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BackgroundNiemann-Pick type C disease (NPC) is a neurovisceral lipid storage disorder mainly characterized by unesterified cholesterol accumulation in lysosomal/late endosomal compartments, although there is also an important storage for several other kind of lipids. The main tissues affected by the disease are the liver and the cerebellum. Oxidative stress has been described in various NPC cells and tissues, such as liver and cerebellum. Although considerable alterations occur in the liver, the pathological mechanisms involved in hepatocyte damage and death have not been clearly defined. Here, we assessed hepatic tissue integrity, biochemical and oxidative stress parameters of wild-type control (Npc1 +/+; WT) and homozygous-mutant (Npc1 −/−; NPC) mice. In addition, the mRNA abundance of genes encoding proteins associated with oxidative stress, copper metabolism, fibrosis, inflammation and cholesterol metabolism were analyzed in livers and cerebella of WT and NPC mice.Methodology/Principal FindingsWe analyzed various oxidative stress parameters in the liver and hepatic and cerebellum gene expression in 7-week-old NPC1-deficient mice compared with control animals. We found signs of inflammation and fibrosis in NPC livers upon histological examination. These signs were correlated with increased levels of carbonylated proteins, diminished total glutathione content and significantly increased total copper levels in liver tissue. Finally, we analyzed liver and cerebellum gene expression patterns by qPCR and microarray assays. We found a correlation between fibrotic tissue and differential expression of hepatic as well as cerebellar genes associated with oxidative stress, fibrosis and inflammation in NPC mice.Conclusions/SignificanceIn NPC mice, liver disease is characterized by an increase in fibrosis and in markers associated with oxidative stress. NPC is also correlated with altered gene expression, mainly of genes involved in oxidative stress and fibrosis. These findings correlate with similar parameters in cerebellum, as has been previously reported in the NPC mice model.

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Section: Discussionmentioning

confidence: 73%

Alteration of Gene Expression Profile in Niemann-Pick Type C Mice Correlates with Tissue Damage and Oxidative Stress

et al. 2011

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“…41,45 Our results using staurosporine and SP600125 (JNK inhibitor) clearly showed that phosphorylation of JNK, but not MEK, regulates ethanol-mediated CYP2E1 induction in U937 monocytes and SVGA astrocytes. Consistent with the previous observation, 23 our finding also suggest that PKCz is the major subtype of PKC family that mediates JNK activation.…”

Section: Discussionmentioning

confidence: 78%

“…The activation of PKC by increased oxidative stress leads to phosphorylation of downstream proteins and induction of downstream signaling cascades. [39][40][41] Previous studies have shown that ethanol can induce multiple signaling cascades and transcription factors, such as mitogen-associated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), which have important roles in cytokine release and the induction of inflammation. 42 Other studies have shown that lipopolysaccharide-mediated CYP2E1 induction in astrocytes is associated with activation of MEK3 and C/EBP-b, 43 while in hepatocytes both SP1 and NF-kB are involved in regulation of CYP2E1.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cytochrome P450 2E1 expression by ethanol: Role of oxidative stressmediated PKC/JNK/SP1 pathway

2013

J Bioequiv Availab

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CYP2E1 metabolizes ethanol leading to production of reactive oxygen species (ROS) and acetaldehyde, which are known to cause not only liver damage but also toxicity to other organs. However, the signaling pathways involved in CYP2E1 regulation by ethanol are not clear, especially in extra-hepatic cells. This study was designed to examine the role of CYP2E1 in ethanolmediated oxidative stress and cytotoxicity, as well as signaling pathways by which ethanol regulates CYP2E1 in extra-hepatic cells. In this study, we used astrocytic and monocytic cell lines, because they are important cells in central nervous system . Our results showed that 100 mM ethanol significantly induced oxidative stress, apoptosis, and cell death at 24 h in the SVGA astrocytic cell line, which was rescued by a CYP2E1 selective inhibitor, diallyl sulfide (DAS), CYP2E1 siRNA, and antioxidants (vitamins C and E). Further, we showed that DAS and vitamin C abrogated ethanol-mediated (50 mM) induction of CYP2E1 at 6 h, as well as production of ROS at 2 h, suggesting the role of oxidative stress in ethanol-mediated induction of CYP2E1. We then investigated the role of the protein kinase C/c-Jun N-terminal kinase/specificity protein1 (PKC/JNK/SP1) pathway in oxidative stress-mediated CYP2E1 induction. Our results showed that staurosporine, a non-specific inhibitor of PKC, as well as specific PKCf inhibitor and PKCf siRNA, abolished ethanol-induced CYP2E1 expression. In addition, inhibitors of JNK (SP600125) and SP1 (mithramycin A) completely abrogated induction of CYP2E1 by ethanol in SVGA astrocytes. Subsequently, we showed that CYP2E1 is also responsible for ethanol-mediated oxidative stress and apoptotic cell death in U937 monocytic cell lines. Finally, our results showed that PKC/JNK/SP1 pathway is also involved in regulation of CYP2E1 in U937 cells. This study has clinical implications with respect to alcohol-associated neuroinflammatory toxicity among alcohol users. 1 To a lesser extent, they are also involved in xenobiotic metabolism in other organs, such as intestine, brain, and kidney. CYP2E1 is known to metabolize ethanol in the liver, especially in chronic alcohol users; 2 however, the persistent use of alcohol and resulting alcohol metabolism is known to cause liver toxicity. 3The alcohol metabolism-mediated liver toxicity occurs through the formation of reactive oxygen species (ROS) and the reactive metabolite, acetaldehyde, which ultimately cause DNA damage and lipid and protein oxidations. 4 Low levels of alcohol in occasional or social mild-tomoderate drinkers are metabolized mainly by alcohol dehydrogenase (ADH), which also appears to cause oxidative stress-mediated liver toxicity.5 However, alcohol-inducible CYP2E1 also has an important role in alcohol metabolism and mediate liver impairment among variety of alcohol drinkers. 2Although the role of CYP2E1 in alcohol-mediated liver toxicity is well known, similar studies are limited in extra-hepatic cells, especially cells from the CNS. Results from previous studies have led to the s...

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“…Interestingly, PKCα is activated in cells and tissues undergoing increased oxidative stress-induced disorders27 such as ischemic cerebrovascular disease, hematopoietic malignancy, and specifically in chronic liver disease, where PKCα has been shown to promote hepatic fibrogenesis28. TAOK1, another potential miR-706-targeted gene, is a MAP kinase kinase kinase (MAP3K) that activates the p38 MAPK293031 cascade exacerbating liver fibrosis via overexpression of α-SMA29303132.…”

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confidence: 99%

miR-706 inhibits the oxidative stress-induced activation of PKCα/TAOK1 in liver fibrogenesis

Yin

Guo

Zhang

et al. 2016

Sci Rep

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Oxidative stress induces the activation of liver fibrogenic cells (myofibroblasts), thus promoting the expression of fibrosis-related genes, leading to hepatic fibrogenesis. MicroRNAs (miRNAs) are a new class of small RNAs ~18–25 nucleotides in length involved in post-transcriptional regulation of gene expression. Wound-healing and remodeling processes in liver fibrosis have been associated with changes in hepatic miRNA expression. However, the role of miR-706 in liver fibrogenesis is currently unknown. In the present study, we show that miR-706 is abundantly expressed in hepatocytes. Moreover, oxidative stress leads to a significant downregulation of miR-706, and the further reintroduction of miR-706 inhibits oxidative stress-induced expression of fibrosis-related markers such as α-SMA. Subsequent studies revealed that miR-706 directly inhibits PKCα and TAOK1 expression via binding to the 3′-untranslated region, preventing epithelial mesenchymal transition. In vivo studies showed that intravenous injection of miR-706 agomir successfully increases hepatic miR-706 and decreases α-SMA, PKCα, and TAOK1 protein levels in livers of carbon tetrachloride (CCl4)-treated mice. In summary, this study reveals a protective role for miR-706 by blocking the oxidative stress-induced activation of PKCα/TAOK1. Our results further identify a major implication for miR-706 in preventing hepatic fibrogenesis and suggest that miR-706 may be a suitable molecular target for anti-fibrosis therapy.

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PKC signaling in oxidative hepatic damage

Cited by 43 publications

References 45 publications

Alteration of Gene Expression Profile in Niemann-Pick Type C Mice Correlates with Tissue Damage and Oxidative Stress

Alteration of Gene Expression Profile in Niemann-Pick Type C Mice Correlates with Tissue Damage and Oxidative Stress

Regulation of Cytochrome P450 2E1 expression by ethanol: Role of oxidative stressmediated PKC/JNK/SP1 pathway

miR-706 inhibits the oxidative stress-induced activation of PKCα/TAOK1 in liver fibrogenesis

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