Silencing of Hepatic AATF Ameliorates Metabolic Dysfunction Associated Steatohepatitis by Promoting Fatty Acid β-Oxidation in Experimental models

Abstract

Background & aimsMetabolic dysfunction-associated steatohepatitis (MASH) is a multifactorial disease driven by complex molecular mechanisms. Identifying key regulators is critical for developing targeted therapies. Here, we demonstrate the impact of the loss of apoptosis antagonizing transcription factor (AATF) on hepatic lipid metabolism and MASH progression. MethodsA preclinical mouse model recapitulating human MASH was established by feeding C57Bl/6 mice either a chow diet (CD) or a western diet with sugar water (WD). Hepatic AATF silencing was achieved by tail vein injection of siAATF delivered by adeno-associated virus 8 (AAV8) with the liver-specific thyroxine-binding globulin (TBG) promoter. In addition to histological, biochemical, and molecular biology evaluations, the mechanistic insights were derived from whole transcriptomics and untargeted metabolomics analyses. ResultsAAV8-mediated specific knockdown of AATF in hepatocytes significantly reduced body weight, liver weight, and insulin resistance in mice fed with western diet (WD). However, no such effects were observed in mice fed with a chow diet (CD). Further analyses showed reduced liver injury, steatosis, and steatohepatitis in WDsiAATF mice. Transcriptomic analysis demonstrated that loss of AATF alleviated cellular stress, inflammation, and fibrosis in WD-fed mice. Moreover, AATF silencing led to alterations in lipid metabolism, notably by decreasing hepatic lipogenesis in the WD mice. Interestingly, untargeted metabolomics revealed an increase in the biosynthesis of glycerophospholipids and beta-oxidation of fatty acids in WDsiAATF mice. ConclusionOur findings reveal a previously unrecognized role of AATF as a central regulator of hepatic lipid metabolism in MASH, acting through the AKT-mTORC1 signaling pathway, and establish its inhibition as a promising therapeutic strategy for metabolic liver disease.