Inhibition of ATGL alleviates NASH in diabetic mice via impaired PPARA signalling

Our present work uncovers that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis, improves NASH and associated key features of metabolic dysfunction in diabetic and hyperlipidaemic mice as a model of NASH. Mechanistically, we demonstrated that attenuation of Ppar signalling in the liver and gut favours hydrophilic bile acids, ultimately interfering with dietary lipid absorption. One of the drawbacks of Atglistatin is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition in human primary ileum-derived organoids, Caco2, and HEPG2 cells translated into similar effects as the Atglistatin and therefore opens a new clinical avenue for NAFLD/MASLD clinical trial and treatment by inhibiting human ATGL activity. Sequencing was performed at the Joint Microbiome Facility of the Medical University of Vienna and the University of Vienna under the project ID JMF-2309-07.