Epigenetics of Nonalcoholic Fatty Liver Disease: Deregulation of Liver Acetylome Enzymes might explain the molecular link between NAFLD and Metabolic Syndrome

FERNANDEZ GIANOTTI T; CASTANO GO; PIROLA CJ; SOOKOIAN S

San Francisco

Congreso; 69th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2019; 2018

American Association for the Study of Liver Diseases

Background: Nonalcoholic fatty liver disease (NAFLD) andmetabolic syndrome (MetS), including cardiovascular disease and type 2 diabetes(T2D), share not only environmental risk factors but a genetic predisposition. Epigeneticmechanisms modulate the interface between the environment and the genome byaffecting gene expression. Particularly critical are the histonemodifications (acetylation/deacetylation), which influence chromatin structureand the access to the transcriptional machinery. Nevertheless, there is a paucityof data examining the role of histone acetyltransferases (HATs) andhistone deacetylases (HDACs) in human NAFLD and its systemic effects.  Aim: We hypothesize thatliver-specific epigeneticchanges, including the balance between protein acetylation and deacetylation, may modulate the disease severity andMetS-related phenotypes. Methods: We used fresh-samplesof liver tissue obtained from patients (NAFLD n=23) and controls (subjectswith near-normal liver-histology, n=14) at the time ofliver biopsy. Nuclearproteins were extracted with EpiQuickNuclear-Extraction Kit; the amount of acetylated or deacetylatedhistones, which is directlyproportional to HAT or HDAC enzymatic activity was assessedin duplicates using colorimetric assays (EpiQuick-HAT Activity/inhibition andHDAC Activity/inhibition Assay kits, Epigentek). Results: Total HAT-activitywas significantly associated with NAFLD (2.07-fold, p = 0.013) but not the disease severity. We tested whether liver-HAT activity was related with the components of the MetS and we observed thatthe level of total HAT-enzyme activity wassignificantly 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 levelssignificantly correlated with the level of glucose-related traits (plasmaglucose: Spearman R:0.35, p=0.03 andHb1C: 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 (whichleads to transcription repression) and NAFLD or MetS-phenotypes. Conclusion:Collectively, our findings show that acetylome-associatedenzymatic activities are deregulatedin the liver tissue of patients with NAFLD. HAT-activity, which promotes genetranscription, may play an important role. Therefore, epigenetic changes mayexplain the cross-talk between the liver and MetS-components.