In fact, T3 induced β-catenin-TCF4 reporter activity both in vitro and in vivo. Livers from T3-treated mice demonstrated
no changes in Ctnnb1 expression, activity of glycogen synthase kinase-3β, known to phosphorylate and eventually promote β-catenin degradation, or E-cadherin-β-catenin association. However, T3 treatment increased β-catenin phosphorylation at Ser675, an event downstream of Selleck Cetuximab protein kinase A (PKA). Administration of PKA inhibitor during T3 treatment of mice and rats as well as in cell culture abrogated Ser675-β-catenin and simultaneously decreased cyclin-D1 expression to block hepatocyte proliferation. Conclusion: We have identified T3-induced hepatocyte mitogenic response to be mediated by PKA-dependent β-catenin activation. Thus, T3 may be of therapeutic
relevance Talazoparib manufacturer to stimulate β-catenin signaling to in turn induce regeneration in selected cases of hepatic insufficiency. (Hepatology 2014;59:2309–2320) “
“Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, whereas inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin (IL)-10, a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic before fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5% ethanol for 4 weeks or a high-fat diet (HFD) for 12 weeks, respectively.
IL-10 knockout (IL-10−/−) mice and several other strains of genetically modified mice were generated and used. Compared with wild-type mice, IL-10−/− mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or HFD feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10−/− mice. In addition, the hepatic expression of sterol regulatory element-binding protein 1 and key downstream lipogenic proteins and enzymes in fatty acid synthesis were down-regulated in IL-10−/− mice. Conversely, IL-10−/− mice displayed enhanced levels of phosphorylated adenosine monophosphate-activated protein kinase and its downstream targets including phosphorylated acetyl-coenzyme A carboxylase and carnitine palmitoyltransferase 1 in the liver. Such dysregulations were corrected in IL-10−/−IL-6−/− or IL-10−/−STAT3Hep−/− double knockout mice. Conclusion: IL-10−/− mice are prone to liver inflammatory response but are resistant to steatosis and hepatocellular damage induced by ethanol or HFD feeding.