Brahma-related gene 1 bridges epigenetic regulation of proinflammatory cytokine production to steatohepatitis in mice

Abstract

Chronic inflammation, inflicted by the spillover of proinflammatory mediators, links metabolic dysfunction to nonalcoholic steatohepatitis (NASH). The epigenetic maneuverings that underscore accelerated synthesis of proinflammatory mediators in response to nutritional inputs are not clearly defined. Here we report that the ATP-dependent chromatin remodeling proteins Brahma-related gene 1 (Brg1) and Brahma (Brm) were up-regulated in vitro in cultured hepatocytes treated with free fatty acid or glucose and in vivo in animal models of NASH. Occupancy of Brg1 and Brm on the promoter regions of proinflammatory genes was increased in vitro in cells and ex vivo in liver tissues. Estradiol suppressed the induction and recruitment of Brg1/Brm by palmitate. Recruitment of Brg1 and Brm relied on nuclear factor kappa B/p65; reciprocally, Brg1 and Brm contributed to the stabilization of p65 binding. Importantly, overexpression of Brg1/Brm enhanced, whereas knockdown of Brg1/Brm attenuated, the induction of proinflammatory mediators in hepatocytes challenged with excessive nutrient. Mechanistically, Brg1 and Brm were involved in the maintenance of a chromatin microenvironment marked by active histone modifications and friendly to the access of the general transcriptional machinery. Finally, depletion of Brg1/Brm by short hairpin RNA attenuated the release of proinflammatory mediators in the liver and significantly ameliorated hepatic pathology in NASH mice. Our data illustrate a Brg1-dependent pathway that connects the epigenetic regulation of proinflammatory genes to the pathogenesis of NASH and point to a potential druggable target in the therapeutic intervention of NASH.