PKC? as a regulator for TGF?1-induced ?-SMA production in a murine nonalcoholic steatohepatitis model.

ABSTRACT: The precise mechanism of TGF?1 signaling in the progression of non-alcoholic steatohepatitis (NASH) has remained unclear. In particular, a potential regulatory mechanism by which PKC? affects profibrogenic gene expression had never been explored. In this study, therefore, the role of PKC? in TGF?1 mediated ?-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 TGF?1 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 ?-SMA expression but also phospho-PKC? in this model. In contrast, Tlr4(Lps-d) (CH3/HeJ) and blockade of TGF?1 receptor by SB431542 resulted in a significant reduction of PKC? activation and ?-SMA expression. Moreover, the TGF?1-induced ?-SMA production was significantly reduced by a specific PKC? inhibitor. These findings suggested that PKC? plays a critical role in TGF?1-induced ?-SMA production in a NASH model. Thus, this was the first demonstration of the involvement of PKC? in the regulation of ?-SMA expression in NASH liver tissues, and the impaired induction of PKC? phosphorylation by LPS in a steatohepatitis condition. Interestingly, treatment by PKC? inhibitor caused dramatic reduction of myofibroblast activation, indicating that PKC? represents a promising target for treating NASH.

SUBMITTER: Lee SJ 

PROVIDER: S-EPMC3575342 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature