Deregulation of Liver Acetylome Enzymes might explain the molecular link between NAFLD and Metabolic Syndrome

TOMAS FERNANDEZ GIANOTTI; CARLOS J. PIROLA; SILVIA SOOKOIAN; GUSTAVO O CASTAÑO

San Francisco

Congreso; The Liver Meeting 2018; 2018

the American Association for the Study of Liver Diseases

Background: Nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS), including cardiovascular disease and type 2 diabetes (T2D), share not only environmental risk factors but a genetic predisposition. Epigenetic mechanisms modulate the interface between the environment and the genome by affecting gene expression. Particularly critical are the histone modifications (acetylation/deacetylation), which influence chromatin structure and the access to the transcriptional machinery. Nevertheless, there is a paucity of data examining the role of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in human NAFLD and its systemic effects. Aim: We hypothesize that liver-specific epigenetic changes, including the balance between protein acetylation and deacetylation, may modulate the disease severity and MetS-related phenotypes. Methods: We used fresh-samples of liver tissue obtained from patients (NAFLD n=23) and controls (subjects with near-normal liver-histology, n=14) at the time of liver biopsy; 37 patients. Nuclear proteins were extracted with EpiQuick Nuclear-Extraction Kit; the amount of acetylated or deacetylated histones, which is directly proportional to HAT or HDAC enzymatic activity was assessed in duplicates using colorimetric assays (EpiQuick-HAT Activity/inhibition and HDAC Activity/inhibition Assay kits, Epigentek). Results: Total HAT-activity was significantly associated with NAFLD (2.07 fold, p = 0.013) but not disease severity. We tested whether liver-HAT activity was related with the components of the MetS and we observed that the level of total HAT-enzyme activity was significantly associated with the presence of T2D (3.31 fold, p=0.012), obesity (2.11 fold, p=0.027), and arterial hypertension (2.30 fold, p=0.008).Then, liver-HAT activity levels significantly correlated with the level of glucose-related traits (plasma glucose: Spearman R:0.35, p=0.03 and Hb1C: R:0.40, p=0.04), CVD-traits (systolic arterial blood pressure: R:0.50, p=0.003), and body mass index (R:0.36, p=0.03). In contrast, we found no association between total HDAC-levels (which leads to transcription repression) and NAFLD or MetS-phenotypes. Conclusion: Collectively, our findings show that acetylome-associated enzymatic activities are deregulated in the liver tissue of patients with NAFLD. HAT-activity, which promotes gene transcription, may play an important role. Therefore, epigenetic changes may explain the liver and MetS cross-talk.