A Cross Talk Between BRG1 and Males Absent on the First Contributes to Reactive Oxygen Species Production in a Mouse Model of Nonalcoholic Steatohepatitis

Aims: Accumulation of reactive oxygen species (ROS) in hepatocytes in response to excessive nutrients and the ensuing liver damages caused by ROS constitute a key pathophysiological event in nonalcoholic steatohepatitis (NASH). In the present study, we investigated the epigenetic mechanism underlying ROS production in NASH pathogenesis. Results: NASH was induced by feeding the mice with a methionine-and-choline-deficient (MCD) diet for 4 weeks. Compared with the control mice (wild type [WT]), mice with hepatocyte-specific deletion of Brg1 (HepcKO), a core component of the mammalian chromatin remodeling complex, developed a less severe form of NASH when fed on the MCD diet. Importantly, ROS levels were attenuated in HepcKO mice as opposed to WT mice. Brahma-related gene 1 (Brg1) deficiency downregulated the transcription of NADPH oxidases (NOX1, NOX2, and NOX4) both in vivo and in vitro. Mechanistically, Brg1 deletion rendered a more repressive chromatin structure surrounding the NOX promoters as characterized by reduced levels of acetylated histones. In addition, Brg1 interacted with the histone H4K16 acetyltransferase males absent on the first (MOF) to activate NOX transcription. MOF knockdown by small interfering RNA or pharmaceutical inhibition by MG149 suppressed NOX transcription and ameliorated ROS levels. Innovation: Our data highlight a novel epigenetic mechanism through which Brg1 and MOF cooperate to regulate ROS production in hepatocytes in response to pro-NASH stimuli. Conclusion: A cross talk between Brg1 and MOF epigenetically activates NOX transcription and elevates ROS synthesis contributing to NASH pathogenesis.