The chromatin remodeling protein BRG1 contributes to liver ischemia-reperfusion injury by regulating NOXA expression

Aims: Hepatic ischemia-reperfusion injury (IRI) is a common complication secondary to liver transplantation. Extensive death of hepatocytes, typically in the form of apoptosis, is observed in and contributes to IRI. In the present study we investigated the role of BRG1 (encoded by Smarca4), a chromatin remodeling protein, in the pathogenesis of liver IRI focusing on the transcriptional mechanism and translational potential.

Methods: Smarca4^f/f mice were crossed to Alb-Cre mice to generate hepatocytes-specific BRG1 knockout mice (CKO). Alterations in cellular transcriptome were evaluated by RNA-seq.

Results: BRG1 expression was up-regulated in liver tissues of mice subjected to I/R and in hepatocytes exposed to hypoxia-reoxygenation (H/R). Compared to wild type (WT) littermates, the BRG1 CKO mice displayed significant amelioration of liver injury following ischemia-reperfusion as evidenced by decreased ALT/AST levels and cell apoptosis. Primary hepatocytes isolated from the CKO mice were protected from H/R-induced apoptosis compared to those from the WT mice. RNA-seq analysis revealed phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA) as a novel target for BRG1. Consistently, NOXA knockdown attenuated liver IRI in mice. More importantly, administration of a small-molecule BRG1 inhibitor (PFI-3) protected the mice from liver IRI.

Conclusions: Our data uncover a pivotal role for BRG1 in liver IRI and suggest that targeting BRG1 with small-molecule inhibitors can be considered as a reasonable therapeutic strategy.