Lipopolysaccharide stimulates endogenous β-glucuronidase via PKC/NF-κB/c-myc signaling cascade: a possible factor in hepatolithiasis formation
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Hepatolithiasis is commonly encountered in Southeastern and Eastern Asian countries, but the pathogenesis mechanism of stone formation is still not well understood. Now, the role of endogenous β-glucuronidase in pigment stones formation is being gradually recognized. In this study, the mechanism of increased expression and secretion of endogenous β-glucuronidase during hepatolithiasis formation was investigated. We assessed the endogenous β-glucuronidase, c-myc, p-p65, and p-PKC expression in liver specimens with hepatolithiasis by immunohistochemical staining, and found that compared with that in normal liver samples, the expression of endogenous β-glucuronidase, c-myc, p-p65, and p-PKC in liver specimens with hepatolithiasis significantly increased, and their expressions were positively correlated with each other. Lipopolysaccharide (LPS) induced increased expression of endogenous β-glucuronidase and c-myc in hepatocytes and intrahepatic biliary epithelial cells in a dose- and time-dependent manner, and endogenous β-glucuronidase secretion increased, correspondingly. C-myc siRNA transfection effectively inhibited the LPS-induced expression of endogenous β-glucuronidase. Furthermore, NF-κB inhibitor pyrrolidine dithiocarbamate or PKC inhibitor chelerythrine could effectively inhibit the LPS-induced expression of c-myc and endogenous β-glucuronidase, and the expression of p-p65 was also partly inhibited by chelerythrine. Our clinical observations and experimental data indicate that LPS could induce the increased expression and secretion of endogenous β-glucuronidase via a signaling cascade of PKC/NF-κB/c-myc in hepatocytes and intrahepatic biliary epithelial cells, and endogenous β-glucuronidase might play a possible role in the formation of hepatolithiasis.
KeywordsHepatolithiasis β-Glucuronidase c-Myc NF-κB
Nuclear factor kappa B
Protein kinase C
This work was funded by National Natural Science Foundation of China (81400659).
YD and DQ performed experiments; YD and TY analyzed data, interpreted results of experiments, and prepared figures; YD, DC, and WS designed the overall study; YD drafted manuscript; DC and WS approved final version of manuscript.
Compliance with ethical standards
Conflict of interest
No conflicts of interest, financial or otherwise, are declared by the authors.
The study was reviewed and approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University (reference number: 2012PS34K) and written informed consent was obtained from all patients, and performed in accordance with the principles outlined in the Declaration of Helsinki.
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