Y27632 prevented the morphological change (aspect ratio 2.1 +/− 0.1, p >.05 vs untreated) indicating that this effect depends on rho-kinase activation. In conclusion, Proteasome inhibitor shh in MP from apoptotic T cells has significant effects on vascular endothelial that are mediated by activation of rho-kinase. We propose that MP may be a significant modulator of impaired hepatic vascular regulation in inflammation and sepsis. Disclosures: Mark G. Clemens – Management Position: HepatoSys Inc; Stock Shareholder: HepatoSys Inc The following people have

nothing to disclose: Samantha A. Canipe, Nicole Feilen, Didier Dreau Aim: To examine the differential effects of chronic dietary iron overload and acute iron excess on nonalcoholic steatosis (NASH) pathogenesis in a genetically obese animal model. Methods: Leprdb/db mice were fed either a normal or iron-supplemented (2% carbonyl iron) chow for 8 weeks. A subset of chow-fed mice were administered a single dose of 1.25 mg/g wt Fe-dextran by IP injection prior R788 mw to resuming NC feeding. The treatment groups are: 1) NC 2) Dietary iron (DI) 3) Par-enteral iron (PI). After 16 weeks, blood and liver tissue were collected. Histological features of NASH and iron deposition were scored by a hepatopathologist

using NASH CRN criteria. Liver transaminase levels, glucose and iron parameters were measured in serum; whereas triglyceride levels, malondialdehyde (MDA), MCE公司 TUNEL staining, immunohistochemistry for 4HNE and changes in gene expression were assessed

in liver tissue. Results: Administration of iron by either route (oral or parenteral), resulted in increased liver enzymes (AST and ALT), glucose and hepatic MDA. Administration of iron by either route also resulted in reduced body mass, increased hepatic iron stores and hepatic hepcidin expression. PI mice had a mixed pattern of hepatocellular (HC) and reticuloendothelial cell system (RES) iron deposition, while DI mice had an exclusively RES localization. PI mice had higher grades of HC and RES iron, decreased steatosis but high inflammation scores. Consistent with the NASH histology, livers of PI mice demonstrated a decrease in the lipid metabolism genes such as TFAM, ACOX, CPT1 α, SREBP1c and SCD1, and an increase in inflammatory/ immune markers such as TLR4, MCP-1, CD68, CD4 and MHCII. Livers from PI mice showed elevated levels of 4-HNE staining. Hepatocellular ballooning was not observed in PI mice, but was significantly elevated in DI mice. DI mice exhibited significantly higher hepatic triglycerides and elevated expression for HO-1 and Gpx-1 anti-oxidant genes. TUNEL staining revealed that PI caused significant apoptosis, higher levels of cleaved caspase-8 protein and increased levels of Bcl2 and Bax genes, relative to NC. Conclusions: Iron supplementation results in an exacerbated diabetic phenotype, increased aminotransferases and oxidative stress in the liver.

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