Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice
Despite the recent approval of drugs novel mechanistic insights and pathophysiology-oriented therapeutic options for MASLD (metabolic dysfunction-associated steatotic liver disease) are still urgently needed. Herein, we show that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis, using atglistatin (ATGLi), improves MASH (metabolic dysfunction-associated steatohepatitis), fibrosis, and key features of metabolic dysfunction in mouse models of MASH and liver fibrosis. Mechanistically, we demonstrated that attenuation of PPARα signalling in the liver and gut favours hydrophilic bile acid composition, ultimately interfering with dietary lipid absorption. One of the drawbacks of ATGLi is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition using the human inhibitor NG-497 in human primary ileum-derived organoids, Caco2 cells, and HepG2 cells translated into therapeutic mechanisms similar to ATGLi. Collectively, these findings reveal a possible new avenue for MASLD treatment.
Authors
- Tatjana Stojaković (ORCID: https://orcid.org/0000-0001-9909-9749)
- Joana Séneca (ORCID: https://orcid.org/0000-0003-3951-3674)
- Georg Busslinger (ORCID: https://orcid.org/0000-0002-7851-9895)
- Alexander D Nardo (ORCID: https://orcid.org/0000-0003-1895-7161)
- G Grabner (ORCID: https://orcid.org/0000-0002-7110-9957)
- Emmanuel D. Dixon (ORCID: https://orcid.org/0000-0002-4120-7441)
- Henkjan J. Verkade (ORCID: https://orcid.org/0000-0002-7034-2861)
- Guenter Haemmerle (ORCID: https://orcid.org/0000-0001-9900-5896)
- Dagmar Kratky (ORCID: https://orcid.org/0000-0003-1357-7573)
- Thierry Claudel (ORCID: https://orcid.org/0000-0002-5601-9830)
- Robert Zimmermann (ORCID: https://orcid.org/0000-0002-7354-870X)
- Veronika Mlitz (ORCID: https://orcid.org/0000-0002-1431-2270)
- Michael A Trauner (ORCID: https://orcid.org/0000-0002-1275-6425)
- Alessandra Riva (ORCID: https://orcid.org/0000-0002-5724-7616)
- Helga Hinteregger
- Claudia Fuchs (ORCID: https://orcid.org/0000-0002-0636-1320)
- Hubert Schnarnagl
Institutions
- University of Vienna (AT)
- University Medical Center Groningen (NL)
- Austrian Academy of Sciences (AT)
- University of Graz (AT)
- Medical University of Graz (AT)
- CeMM Research Center for Molecular Medicine (AT)
- Ludwig Boltzmann Institute Applied Diagnostics (AT)
- Technical University of Munich (DE)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Journal of Hepatology
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1016/j.jhep.2024.09.037
- Citations
- 32
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 7.48
Funders
- Austrian Science Fund