PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model.
The precise mechanism of TGFβ1 signaling in the progression of non-alcoholic steatohepatitis (NASH) has remained unclear. In particular, a potential regulatory mechanism by which PKCδ affects profibrogenic gene expression had never been explored. In this study, therefore, the role of PKCδ in TGFβ1 m...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3575342?pdf=render |
| _version_ | 1818912237876674560 |
|---|---|
| author | Su Jin Lee Jeong Han Kang Soo Young Choi Ki Tae Suk Dong Joon Kim Oh-Shin Kwon |
| author_facet | Su Jin Lee Jeong Han Kang Soo Young Choi Ki Tae Suk Dong Joon Kim Oh-Shin Kwon |
| author_sort | Su Jin Lee |
| collection | DOAJ |
| description | The precise mechanism of TGFβ1 signaling in the progression of non-alcoholic steatohepatitis (NASH) has remained unclear. In particular, a potential regulatory mechanism by which PKCδ affects profibrogenic gene expression had never been explored. In this study, therefore, the role of PKCδ in TGFβ1 mediated α-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 TGFβ1 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 α-SMA expression but also phospho-PKCδ in this model. In contrast, Tlr4(Lps-d) (CH3/HeJ) and blockade of TGFβ1 receptor by SB431542 resulted in a significant reduction of PKCδ activation and α-SMA expression. Moreover, the TGFβ1-induced α-SMA production was significantly reduced by a specific PKCδ inhibitor. These findings suggested that PKCδ plays a critical role in TGFβ1-induced α-SMA production in a NASH model. Thus, this was the first demonstration of the involvement of PKCδ in the regulation of α-SMA expression in NASH liver tissues, and the impaired induction of PKCδ phosphorylation by LPS in a steatohepatitis condition. Interestingly, treatment by PKCδ inhibitor caused dramatic reduction of myofibroblast activation, indicating that PKCδ represents a promising target for treating NASH. |
| first_indexed | 2024-12-19T23:11:25Z |
| format | Article |
| id | doaj.art-2d04d045c6c84d98b64eac23f0854bfb |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T23:11:25Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2d04d045c6c84d98b64eac23f0854bfb2022-12-21T20:02:12ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0182e5597910.1371/journal.pone.0055979PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model.Su Jin LeeJeong Han KangSoo Young ChoiKi Tae SukDong Joon KimOh-Shin KwonThe precise mechanism of TGFβ1 signaling in the progression of non-alcoholic steatohepatitis (NASH) has remained unclear. In particular, a potential regulatory mechanism by which PKCδ affects profibrogenic gene expression had never been explored. In this study, therefore, the role of PKCδ in TGFβ1 mediated α-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 TGFβ1 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 α-SMA expression but also phospho-PKCδ in this model. In contrast, Tlr4(Lps-d) (CH3/HeJ) and blockade of TGFβ1 receptor by SB431542 resulted in a significant reduction of PKCδ activation and α-SMA expression. Moreover, the TGFβ1-induced α-SMA production was significantly reduced by a specific PKCδ inhibitor. These findings suggested that PKCδ plays a critical role in TGFβ1-induced α-SMA production in a NASH model. Thus, this was the first demonstration of the involvement of PKCδ in the regulation of α-SMA expression in NASH liver tissues, and the impaired induction of PKCδ phosphorylation by LPS in a steatohepatitis condition. Interestingly, treatment by PKCδ inhibitor caused dramatic reduction of myofibroblast activation, indicating that PKCδ represents a promising target for treating NASH.http://europepmc.org/articles/PMC3575342?pdf=render |
| spellingShingle | Su Jin Lee Jeong Han Kang Soo Young Choi Ki Tae Suk Dong Joon Kim Oh-Shin Kwon PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model. PLoS ONE |
| title | PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model. |
| title_full | PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model. |
| title_fullStr | PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model. |
| title_full_unstemmed | PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model. |
| title_short | PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model. |
| title_sort | pkcδ as a regulator for tgfβ1 induced α sma production in a murine nonalcoholic steatohepatitis model |
| url | http://europepmc.org/articles/PMC3575342?pdf=render |
| work_keys_str_mv | AT sujinlee pkcdasaregulatorfortgfb1inducedasmaproductioninamurinenonalcoholicsteatohepatitismodel AT jeonghankang pkcdasaregulatorfortgfb1inducedasmaproductioninamurinenonalcoholicsteatohepatitismodel AT sooyoungchoi pkcdasaregulatorfortgfb1inducedasmaproductioninamurinenonalcoholicsteatohepatitismodel AT kitaesuk pkcdasaregulatorfortgfb1inducedasmaproductioninamurinenonalcoholicsteatohepatitismodel AT dongjoonkim pkcdasaregulatorfortgfb1inducedasmaproductioninamurinenonalcoholicsteatohepatitismodel AT ohshinkwon pkcdasaregulatorfortgfb1inducedasmaproductioninamurinenonalcoholicsteatohepatitismodel |