The Impact of Silencing Hepatic AATF on Transcriptomic and Metabolomic Signatures in Experimental MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 30% of the global population and has emerged as a significant public health concern. It is a multifactorial pathological condition driven by various molecular influencers. Thus, identifying and understanding the molecular drivers of MASLD pathogenesis is essential for developing targeted therapeutic strategies. Here, we elucidate the role of apoptosis antagonizing transcription factor (AATF) as a molecular driver in the pathogenesis of MASLD. Liver-specific silencing of AATF reduced body weight, liver weight, and insulin resistance in WD mice compared to WD controls. Biochemical, histological, and molecular analyses showed reduced liver injury, and steatosis. Transcriptomics analysis showed reduced cellular stress response, inflammation and fibrosis in WDsiAATF. Furthermore, untargeted metabolomics revealed increased biosynthesis of glycerophospholipids and promoted fatty acid oxidation while reducing the triglyceride accumulation. These findings show a molecular link between AATF and hepatic lipid metabolism, implying that AATF could be a promising therapeutic target for MASLD. Overall design: We used adeno-associated vectors (AAV) to create a liver-specific AATF knockdown model in C57bl6 mice in order to study the molecular involvement of AATF in metabolic dysfunction-associated steatohepatitis (MASH). For 12 weeks, the mice were fed either chow diet normal water or western diet sugar water to create diet-induced MASH models. AAV carrying siAATF or null was injected into the mice via tail vein at week 12, and they were observed for an additional 12 weeks. Gene expression analysis was done using RNA sequencing in liver tissues obtained at the end of the study from four groups. Three replicates were used in the analysis. Comparisons were made between Western Diet Control (WDC) and Chow Diet Control (CDC), Western Diet siAATF (WDsiAATF) and Western Diet control (WDC), and chow diet siAATF (CDsiAATF) and chowe diet control (CDC).