The liver content of BiP was elevated in alcohol-fed livers compared to control. The content of GRP94 was comparable
between all experimental groups, while GRP78/ BiP was elevated in alcohol Crizotinib order exposed animals regardless of LPS exposure. CHOP was elevated in LPS-exposed liver however there was no further modulation by alcohol. Similar to CHOP, LPS induced p-c-Jun; in contrast to CHOP, alcohol significantly inhibited its expression in liver. In vitro, alcohol-exposed Hepa 1.6 cells, used as model hepatocytes, had higher background calcium flux. Stimulation with LPS caused sharp calcium flux to intracellular compartment. Of importance, alcohol-exposed Hepa 1.6 cells showed delayed dynamics of intracellular calcium flux in response to LPS compared to alcohol-naive counterparts. These results suggested that alcohol LBH589 mw and LPS, independently of each other, cause significant
intracellular calcium flux and modulate calcium-dependent reticulum stress, yet together they lead to URP and inflammation. More importantly, we identified that XBP-1 and p-eIF2a/ATF4 pathways are likely protective and BiP pathways is likely detrimental to alcohol-induced hepatocyte damage. In conclusion, we report novel finding that differential targeting of UPR either by upregulation of XBP-1 and p-eIF2a/ATF4, or by downregulation of BiP, may have translational potential for protection against ADL in mice. Disclosures: The following people have nothing to disclose: Ureohydrolase Keisaku Sato, Tracie C. Lo, Angela Dolganiuc BACKGROUND: Alcoholic hepatitis (AH) is a major indication for liver-related hospitalizations. There are limited data on the changes in clinical and epidemiological profile of patients admitted for AH and their outcomes over the last decade. AIMS: To determine the changing profile of subjects admitted for AH over time in the US with respect to: (1) hospitalization rates, (2) demographics, (3) clinical severity, (4) comorbidi-ties, and (5) outcomes. METHODS: A retrospective analysis of adults admitted for AH from 2000-2011 was performed using an anonymized EMR database of patient-level data from 111 US medical centers.
RESULTS: (1) Hospitalizations: AH admission rates remained stable over time (0.06%, total n= 6113 out of 8.1 million admissions). (2) Demographics: The mean age (48 ± 10yrs) remained unchanged; however, the proportion of those ages 40-49yrs among AH admissions decreased (46 to 36%) while those 50-59yrs increased (26 to 31%) (both p<0.0001). Baby boomers accounted for 28-35% of all admissions but almost 65-77% of AH admissions (p<0.0001). Non-Hispanic blacks (NHB) accounted for 17% of all admissions but only 12% of AH admissions (p<0.0001). (3) Clinical: The median MELD score increased from 12 to 14 (Spearman, p=0.0014). This was driven by a modest increase in INR (1.2 to 1.4, p<0.0001) while median bilirubin and creatinine remained stable at 2mg/dL and 0.8mg/dL respectively.