BCAT1 Is Associated with Clinical Decompensation in Nonalcoholic Fatty Liver Disease: a Pilot Study

Abstract

Introduction: NAFLD is the leading cause of chronic liver disease worldwide. Factors predicting poor prognosis remain incompletely understood. Aim: We evaluated whether hepatic gene expression (GEx) and DNA methylation (DM) associated with clinical outcomes with the ultimate goal of identifying molecular markers predicting risk for NAFLD-related morbidity and mortality. Methods: We performed a retrospective analysis of patients with biopsy-proven NAFLD whose biopsies were previously evaluated for GEx and DM via array analysis. Patients were assessed from time of liver biopsy until death, liver transplantation, or study end on July 1, 2015. Outcomes analyzed included decompensation (i.e., ascites, hepatic encephalopathy, hepatocellular carcinoma, or variceal bleeding) and a composite outcome of stroke, myocardial infarction, and death. Associations between the composite outcome, GEx, and DM were quantified using generalized linear models controlling for age, body mass index, diabetes and fibrosis stage. Results: 86 patients were included. Most (67%) were female and white (89%) and the median age at biopsy was 53 years (range, 27 to 81). Median follow up was 1986 days (range 0- 2997). Four patients, all white women, experienced clinical outcomes (two suffered hepatic decompensation, two had strokes). Fibrosis at study entry ranged from stage 1 to 4. 42 genes showed significant differential expression (p < 0.05) and two probes on BCAT1 were upregulated (p=0.02; fold change 2.1 and 2.2). BCAT1 was also hypomethylated in patients with outcomes compared to those without. Principal Component Analysis and hierarchical clustering confirmed GEx aided in differentiating patients with poor outcomes from NAFLD from those without. Conclusion:BCAT1 initiates the catabolism of essential branched chain amino acids and was found to be hypomethylated and upregulated in NAFLD patients with clinical decompensation or cardiovascular outcomes. BCAT1 upregulation has been associated with high liver fat content as well as poor prognosis in hepatocellular carcinoma. Our study suggests that perturbations in hepatic metabolism are associated with poor outcomes in NAFLD and possibly controlled via DM. Further investigation of these targets for their ability to better identify NAFLD patients at increased risk for poor outcomes are needed.Table 1: Selected differentially expressed and DNA methylated genes (p < 0.05) in NAFLD patients with and without clinical outcomes.