| First Author | Lee SJ | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 2 | Pages | e55979 |
| PubMed ID | 23441159 | Mgi Jnum | J:199411 |
| Mgi Id | MGI:5502515 | Doi | 10.1371/journal.pone.0055979 |
| Citation | Lee SJ, et al. (2013) PKCdelta as a regulator for TGFbeta1-induced alpha-SMA production in a murine nonalcoholic steatohepatitis model. PLoS One 8(2):e55979 |
| abstractText | The precise mechanism of TGFbeta1 signaling in the progression of non-alcoholic steatohepatitis (NASH) has remained unclear. In particular, a potential regulatory mechanism by which PKCdelta affects profibrogenic gene expression had never been explored. In this study, therefore, the role of PKCdelta in TGFbeta1 mediated alpha-SMA expression was investigated using NASH model mice. In preparation of the NASH model, male C57BL6/J mice were fed a methionine-choline-deficient (MCD) diet for 3 weeks, after which time they were intraperitoneally injected with lipopolysaccharide (LPS). In addition, Tlr4(Lps-d) (CH3/HeJ) mice were used to demonstrate the TGFbeta1 signaling's dependency on TLR4 induction. Liver histology and hepatic hepatitis markers were investigated, and hepatic gene expression levels were determined by real-time PCR. Acute liver injury by LPS injection specifically elevated not only alpha-SMA expression but also phospho-PKCdelta in this model. In contrast, Tlr4(Lps-d) (CH3/HeJ) and blockade of TGFbeta1 receptor by SB431542 resulted in a significant reduction of PKCdelta activation and alpha-SMA expression. Moreover, the TGFbeta1-induced alpha-SMA production was significantly reduced by a specific PKCdelta inhibitor. These findings suggested that PKCdelta plays a critical role in TGFbeta1-induced alpha-SMA production in a NASH model. Thus, this was the first demonstration of the involvement of PKCdelta in the regulation of alpha-SMA expression in NASH liver tissues, and the impaired induction of PKCdelta phosphorylation by LPS in a steatohepatitis condition. Interestingly, treatment by PKCdelta inhibitor caused dramatic reduction of myofibroblast activation, indicating that PKCdelta represents a promising target for treating NASH. |
