BAG6 is a novel player in controlling nonalcoholic steatohepatitis: result from a comprehensivein-silicostudy

Abstract

SummaryNonalcoholic steatohepatitis, or NASH, is a multifactorial disease characterized by hepatic lipid accumulation, inflammation, cell death, and fibrosis, and an efficacious pharmaceutical intervention for this is yet to be discovered. The present study aims to identify potential targets capable of reversing the disease-specific molecular alterations and elucidate their possible action mechanism. Our study uses combinations of different methods, such as genome-scale metabolic modelling, directional protein-protein interaction network, connectivity map, and network controllability, to identify potential targets in NASH. Our approach yielded three promising targets, BAG6, CASP3, and CYCS, and captured their effects on inflammation, fibrosis, steatosis, and apoptosis. The association of CASP3 and CYCS with NASH are already reported in the literature. So BAG6 was selected as a novel target. In the Huh-7 cell-line, its ablation reduced fatty acid accumulation and decreased levels of NASH-signature transcripts, supporting our hypothesis on BAG6 as a potential NASH target.