Targeting CD147 function during liver injury using mAb, siRNA or genetic knockout in mice significantly reduced hepatocyte MMP production, reduced total ECM production, and resulted in a net reduction in fibrotic ECM, but it also reduced leukocyte aggregation and the extent of the injury. Conclusion: Although leukocyte aggregation is well described as occurring in inflammation, we have uncovered a new CD147 dependent mechanism by which this occurs and impacts on the severity of injury. We furthermore demonstrated that hepatocytes produce active MMPs capable of ECM remodelling in liver fibrosis. And we have shown that this process is regulated by CD147.

CD147 is a powerful player in liver injury and is also found to be highly increased in HCC. A detailed understanding of CD147 function is therefore required for the selective targeting of those processes and has the LY2835219 solubility dmso potential to lead to new therapeutic agents. E ARFIANTI, SS LEE, D HEYDET, C LARTER, V BARN, NC TEOH, GC FARRELL Liver Research Group, ANU Medical School at The Canberra Hospital, ACT Background: Obesity and type 2 diabetes both promote the development of hepatocellular Selleckchem Pifithrin �� carcinoma (HCC), which is an increasingly recognized complication of obesity/diabetes-related non-alcoholic fatty liver disease. We recently reported early onset of diethylnitrosamine (DEN)-induced HCC in obese and diabetic foz/foz NOD.B10 mice which

was associated with hyperinsulinemia, hyperglycemia and perturbed MCE公司 serum adipokine levels, rather than inflammation [JGH 2011; 26 (Suppl):6]. The mammalian target of rapamycin (mTOR), a nutrient-sensitive protein kinase, is abberantly activated in up to 50% of HCC cases. In the present study, we investigate the role of Akt/mTOR signalling pathways during the early (premalignant) stage of hepatocarcinogenesis. Methods Male foz/foz and non-obese heterozygous (foz+/−) littermates

were injected with DEN (10 mg/kg i.p.) at 12–15 days of age; controls were injected with vehicle (saline). At 12 weeks post-DEN injection, dysplastic hepatocytes were identified by glutathione S-transferase pi (GST-pi) immunohistochemistry (IHC). Protein expression of Akt/mTOR signalling intermediates in liver lysates were analysed by immunoblotting and IHC. We also determined the growth inhibitory effect of rapamycin on primary HCC cell culture using cells derived from foz/foz mice using MTT assays. Results: DEN-treated foz/foz mice exhibited a higher number of GST-pi-positive cells compared to respective lean mice (3.7 ± 0.68% vs. 1.6 ± 0.20 %, P < 0.05), reflecting enhanced growth of dysplastic hepatocytes. DEN increased proliferative and apoptosis markers in obese mice, corresponding to the up-regulation of positive cell cycle regulators (cyclins D1, E) and pro-apoptotic Bax, respectively. Interestingly, Akt phosphorylation, an important mediator of insulin signalling, was enhanced in livers from DEN-injected obese mice.