PKR, eIF2α and JNK1 phosphorylation/activation were studied by western blots from liver tissues. Apoptosis was assessed by the active caspase 3 subunit. Fibrosis tested by procollagen a1(I) ASMA, TGFβ expression and hydroxyl proline assay. In vitro, primary wt hepatocytes were exposed to palmitate and NOX4 promoter studies were conducted. Wt hepatocytes were transfected with the PKR siRNA, exposed to palmitate and eiF2a and JNK1 phosphorylation were evaluated. selleck chemicals Results: NO X4 expression was induced in the fl/fl

mice on the CDAA diet (p < 0.05). The TG content significantly improved in the Albcre/NOX4 mice (p<0.01) with the downregulation of SREBP1c, Fas (p = 0.04), and HIF inhibitor PPARγ compared to fl/fl controls. PKR, eIF2α, JNK1

and CHOP activation were significantly attenuated in the Albcre NOX4 mice on the CDAA diet. Hepatocyte apoptosis (active caspase 3) and fibrosis also improved significantly in the NOX4/Albcre mice with lower procollagen α1(I) ASMA, TGFβ expression and hydroxy proline content (p < 0.05). In vitro, palmitate induced NO X4 promoter activity. PKR, eiF2α, JNK1 phosphorylation, and CHOP activation have decreased in the palmitate-treated NOX4-/- hepatocytes. In the PKR siRNA and palmitate treated fl/fl cells JNK1 and eiF2α induction were significantly attenuated. Conclusion: NO X4 induction in hepatocytes by saturated fatty acids contributes to steatosis and to the induction of PKR-mediated stress pathways and cell death during NASH progression. Targeting NO X4 could thus be beneficial to improve hepatocyte injury and fibrosis in NASH. Disclosures: The following people have nothing to disclose: Tzu-I Chao, Xiaosong Jiang, Hiroo Fukada, Fawaz Haj, Ahmed Bettaieb,

Natalie Torok Background: Non-alcoholic steatohepatitis (NASH) is characterized by fat accumulation, chronic inflammation (includingmacrophages) DNA ligase and fibrosis that can lead to cirrhosis or hepatocellular carcinoma. Treatment options are very limited. Recent evidence suggests that C-C chemokine receptor (CCR) type 2 and its main ligand, monocyte chemotactic protein-1, contribute to macrophage recruitment in the liver. Cenicriviroc (CVC) is an oral, potent, dual CCR2/CCR5 antagonist that showed favorable safety and tolerability over 24 weeks of dosing in an ongoing 48-week Phase 2b study in 143 HIV-1-infected adults (NCT01338883). We evaluated CVC in a mouse model of NASH that leads to hepatocellular carcinoma; data from the first, fibrotic stage of the model are presented. Methods: NASH was induced in male mice by a single injection of 200μg streptozotocin 2 days after birth (causing insulin resistance), followed by a high fat diet from 4 weeks of age.