The study of hepatocytes derived from AAT mutant human induced pluripotent stem cells (hIPSC) may overcome this limitation by identifying cellular phenotypes that correlate with clinical severity of disease in existing AAT patients. For this purpose, we have generated hIPSC lines from AAT patients (ZZ) with variable degrees of liver disease, including those without evidence of liver damage and those who have suffered a more aggressive course leading to end stage
liver disease. We are using control and AAT hIPSC-derived hepatocyte like cells (HLCs) to probe the hypothesis that the significant heterogeneity seen in disease progression due to AAT ZZ mutations is related to genetically determined variability of fundamental biological hepatocyte processes involved in cellular selleck inhibitor disposal, stress response, and cell survival pathways. Prior data obtained in mouse and cell line models has shown that autophagy may act as a primary route of intracellular degradation of mutant AAT
protein. Although traditionally regarded as a cellular adaptive process triggered by nutrient deprivation, autophagy in hepatocytes may also provide an important hepatoprotective buy C646 mechanism. Our preliminary results show that HLCs derived from AAT mutant patients with no evidence of liver disease (AAT NLD) have increased activation of autophagy at baseline compared to AAT mutants with severe liver disease (AAT LD). Our data supports a role for autophagy as a potential modifier in the pathobiology of AAT related liver disease and opens the way for mechanistic studies
involving this and other basic biological pathways that may modulate hepatic injury in AAT. Our studies can impact the way we approach AAT deficiency: 1) by developing predictive diagnostics through discovery of biomarkers that identify patients at risk for severe liver disease, and 2) by promoting therapeutic candidate discovery through validation of new or existing therapeutic targets in live human hepatocytes. Disclosures: The following people have nothing to disclose: Tamara Taketani, Maria P. Ordonez, Lawrence S. Reverse transcriptase Goldstein Background: Controlled clinical trials have shown that vitamin E improves liver histology and biochemical profiles in patients with nonalcoholic steatohepatitis. However, its effect in overall NAFLD patients has not been fully elucidated. In this study, we sought to determine the short-term effect of vitamin E, off-treatment durability of response, and predicting factors for vitamin E response in NAFLD patients. Methods: A cohort of 1953 NAFLD patients who visited our outpatient clinic between Jan. 2005 and Mar. 2013 was constructed by using the electronic medical record system (BESTCARE). After excluding comor-bid liver diseases, 257 patients who received vitamin E and 416 control patients were matched for propensity scores. The matched covariates included age, sex, BMI, AST, ALT, presence of DM or dyslipidemia.