title: PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model.
abstract: 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.
authors: School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, Korea.
authors: Su Jin
authors: SJ
authors: Lee
authors: Jeong Han
authors: JH
authors: Kang
authors: Soo Young
authors: SY
authors: Choi
authors: Ki Tae
authors: KT
authors: Suk
authors: Dong Joon
authors: DJ
authors: Kim
authors: Oh-Shin
authors: OS
authors: Kwon
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000199:Actins / Q000096:biosynthesis*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D004032:Diet; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000378:metabolism; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D000098:Acetophenones; D000199:Actins; D001578:Benzopyrans; D008070:Lipopolysaccharides; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; C085746:rottlerin; D051745:Protein Kinase C-delta