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

Abstract

Background: 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 drivers. Thus, identifying and understanding the molecular drivers involved in MASLD pathogenesis is essential for developing targeted therapeutic strategies. Aim: To elucidate the role of apoptosis antagonizing transcription factor (AATF) as a molecular driver in the pathogenesis of MASLD and its underlying mechanisms. Methods: A preclinical murine model resembling human MASLD was employed, in which C57Bl/6 mice were fed either a chow diet with normal water (CD) or a western diet with sugar water (WD). After 12 weeks, mice were injected via the tail vein with AAV8 serotype particles and randomized into four groups: (i) CD with AAV8-TBG-Null, (ii) CD with AAV8-TBG-siAATF, (iii) WD with AAV8-TBG-Null (WD control), and (iv) WD with AAV8-TBG-siAATF (WD siAATF). Biochemical, histological, and molecular analyses were performed using serum and liver tissues. Untargeted metabolomics was carried out in the liver tissues of the experimental MASLD. Results: AATF was upregulated in cellular and preclinical models of MASLD. Liver-specific silencing of AATF reduced body weight, liver weight, and insulin resistance in WD mice compared to WD controls but had no effect on CD mice. Biochemical, histological, and molecular analyses showed reduced liver injury, steatosis, inflammation, and fibrosis in AATF-silenced WD mice. Furthermore, untargeted metabolomics revealed increased levels of glycerophospholipids, such as phosphatidylcholines, phosphatidylserines, and phosphatidylethanolamines, in the WD siAATF mice. Consistently, expression of hepatic carnitine palmitoyl transferase (CPT1) and peroxisome proliferator-activated receptor alpha/gamma (PPAR α/γ), which promote fatty acid beta-oxidation, was upregulated in the WD siAATF compared to WD controls. Conclusion: These findings show a molecular link between AATF and hepatic lipid metabolism, implying that AATF could be a promising therapeutic target for MASLD.