Chromatin remodeler BRD9 represses transcription of PPARα target genes, including CPT1A to suppress lipid metabolism.

Peroxisome proliferator-activated receptor α (PPARα) regulates the transcription of fatty acid oxidation-related genes, such as carnitine palmitoyltransferase 1A (CPT1A), to maintain lipid homeostasis. Recent studies have suggested the involvement of switch/sucrose non-fermentable (SWI/SNF) complexes in nuclear receptor-mediated transcription. SWI/SNF complexes are chromatin remodeling factors classified into three complexes: canonical brahma-related gene 1-/brahma-associated factor (cBAF), polybromo BAF (PBAF), and non-canonical BAF (ncBAF). Among these, the key regulator of PPARα-mediated transcription remains unclear. In this study, we sought to clarify the significance of each SWI/SNF complex in PPARα-mediated transcription. Glycerol sedimentation assay revealed that PPARα interacts with ncBAF. The expression of multiple PPARα target genes, including CPT1A, was increased in HepG2 cells or primary human hepatocytes by inhibition or knockdown of bromodomain-containing protein 9 (BRD9), a specific subunit of ncBAF. Co-immunoprecipitation and pull-down assays demonstrated that PPARα interacts with ncBAF via BRD9. Chromatin immunoprecipitation- and formaldehyde-assisted isolation of regulatory elements-qPCR analyses revealed that BI-9564, an inhibitor of BRD9, can enhance the binding of PPARα to the PPRE on CPT1A by relaxing the chromatin structure. Interestingly, lipid accumulation in free fatty acid-treated HepG2 cells was attenuated by BI-9564 treatment, and the administration of BI-9564 to mice decreased their plasma triglyceride levels. Collectively, this study demonstrated that BRD9 negatively regulates PPARα-mediated transactivation and that inhibition of BRD9 can attenuate lipid accumulation by enhancing hepatic lipid metabolism. Thus, BRD9 could be considered a novel pharmacological target for dyslipidemia.