Abstract
Uncontrolled inflammatory response and augmented lipid accumulation represent two key pathophysiological events in the pathogenesis of non-alcoholic steatohepatitis (NASH). NF-κB and SREBP1c program transcriptional regulation of cellular inflammatory response and lipid metabolism, respectively. The epigenetic mechanism underlying NF-κB-dependent pro-inflammatory transcription and SREBP1c-dependent pro-lipogenic transcription remains incompletely understood. In the present study we investigated the involvement of Brg1, a chromatin remodeling protein, in NASH pathogenesis in a methionine-and-choline deficient diet (MCD) induced mouse model. Brg1 expression was up-regulated in the liver in mice fed on the MCD diet and in primary hepatocytes exposed to free fatty acids. Liver injury and hepatic inflammation attenuated in hepatocyte-specific Brg1 knockout (CKO) mice fed on the MCD diet compared to the wild type (WT) littermates. Likewise, synthesis of pro-inflammatory mediators was down-regulated in primary hepatocytes isolated from CKO mice compared to WT mice, which resulted in reduced macrophage chemotaxis. Brg1 contributed to the transcription of pro-inflammatory mediators possibly by regulating the interaction between NF-κB and its co-factor MRTF-A. On the other hand, accumulation of triglyceride and cholesterol was ameliorated in MCD-fed CKO mice with a concomitant reduction of SREBP1c target genes. Brg1 interacted with SREBP1c and modulated the transcription of SREB1c target genes in the liver in response to MCD feeding by influencing active histone modifications. In conclusion, targeting Brg1 may yield novel anti-NASH therapeutics by simultaneously normalizing hepatic inflammatory status and metabolic profile in NASH patients.