Abstract
Hepatic stellate cells (HSCs) play pivotal roles in hepatic fibrosis as they synthesize glial fibrillary acidic protein (GFAP), which is increased in activated HSCs. GFAP-expressing HSCs and myofibroblasts accumulate in and around hepatic fibrosis lesions. Peptidylarginine deiminase 2 (PAD2) is responsible for the citrullination of GFAP (cit-GFAP). However, the involvement of PAD2 and cit-GFAP in hepatic fibrosis remains unclear. To determine the expression of PAD2 and cit-GFAP in hepatic fibrosis, C57BL/6 mice underwent bile duct ligation (BDL) or a sham operation. In BDL livers, the expression of PAD2 and its enzyme activity were significantly increased compared with controls. In addition, PAD2-postitive cells were rarely observed in only the portal vein and the small bile duct in sham-operated livers, whereas an increased number of PAD2-positive cells were detected in the bile duct and Glisson’s sheath in BDL livers. Interestingly, PAD2 was colocalized with α-SMA-positive cells and CK19-positive cells in BDL livers, indicating upregulated PAD2 in activated HSCs and portal fibroblasts of the livers of BDL mice. We also found that citrullinated proteins were highly accumulated in the livers of BDL mice compared with controls. Moreover, the expression level of GFAP and the amount of cit-GFAP were higher in BDL livers than in control livers. In correlation with PAD2 localization, cit-GFAP was observed in α-SMA-positive and CK19-positive cells in the livers of BDL mice. These results suggest that the increased expression and activation of PAD2 along with increased citrullinated proteins, specifically cit-GFAP, may play important roles in the pathogenesis of hepatic fibrosis.
Highlights
Hepatic fibrosis is induced by various etiologies of chronic hepatitis C virus (HCV) infection, chronic B virus infection, alcoholism, nonalcoholic fatty liver disease, autoimmune diseases and cholestasis, among others [1,2,3]
These results showed that hepatic fibrosis was well developed in our bile duct ligation (BDL) mouse model
We found similar results using the livers from TAA-induced mice the intensity of colocalization of Peptidylarginine deiminase 2 (PAD2) with α-smooth muscle actin (SMA) or CK19 was less than the livers of BDL-induced hepatic fibrosis mice (S2 Fig)
Summary
Hepatic fibrosis is induced by various etiologies of chronic hepatitis C virus (HCV) infection, chronic B virus infection, alcoholism, nonalcoholic fatty liver disease, autoimmune diseases and cholestasis, among others [1,2,3]. Hepatic fibrosis is defined as the result of excessive deposition of extracellular matrix, which disrupts the normal architecture of the liver [2]. Activation of hepatic stellate cells (HSCs) are believed to play a major role in hepatic fibrosis and results in conversion to myofibroblasts [5, 6], which produce extracellular matrix proteins such as collagens. Transformed HSC-derived myofibroblasts from quiescent HSCs by fibrotic stimuli express increased cytoskeletal proteins such as α-smooth muscle actin (α-SMA), vimentin, and desmin [5]. Quiescent HSCs store retinoids and synthesize glial fibrillary acidic protein (GFAP) in normal liver [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
