Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Bradić, I.
Crosstalk of lysosomal lipid degradation in liver and adipose tissue
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kratky Dagmar
- Moustafa Tarek
- Radovic Branislav
- Altmetrics:
- Abstract:
- Lysosomal acid lipase (LAL) is a crucial enzyme that degrades neutral lipids in lysosomes. LAL deficiency (LAL-D) is a disease whose severity depends on the residual LAL activity. Patients with complete loss of LAL activity develop early-onset LAL-D and must be immediately treated; otherwise, they die within the first year of life. One of the main treatment options for early-onset LAL-D patients is enzyme replacement therapy, which restores LAL activity and improves lipid metabolism and inflammation. Late-onset LAL-D patients have some residual LAL activity, so their disease is less severe and often misdiagnosed with other liver diseases, such as non-alcoholic fatty liver disease (NAFLD). In this thesis, I used LAL knockout (Lal-/-) and hepatocyte-specific Lal-/- (hepLal-/-) mice to study LAL-D. Lal-/- develop a severe phenotype affecting multiple organs, whereas hepLal-/- mice present with a mild phenotype mainly impacting the liver. Since Lal-/- mice progressively lose white adipose tissue (WAT), I assessed the impact of LAL-D on adipogenesis and lipogenesis of primary adipocytes utilizing the LAL inhibitor Lalistat 2 (L2). Detailed characterization of adipocytes revealed that LAL-D has no impact on adipogenesis or lipogenesis. However, it was observed that the commonly used LAL inhibitors L2 and L1 inhibit other lipases in addition to LAL. Off-target effects of L2 and L1 already at low concentrations were confirmed in macrophages. Thus, L1 and L2 are not suitable inhibitors to study LAL function and might lead to wrong conclusions in lipid metabolism and autophagy studies. Since lipodystrophy in Lal-/- mice could not be explained by the lack of LAL in WAT, I analyzed the liver proteome of Lal-/- mice but identified no potential candidates to explain the loss of WAT. As expected, livers of Lal-/- mice exhibited increased inflammation and impaired liver lipid metabolism with a massive accumulation of total cholesterol and decreased neutral and acid lipase activities. In contrast, proteomics analysis in hepLal-/- livers showed only minor changes, aligning with a mild phenotype of hepLal-/- mice. To explore additional treatment options for LAL-D, I assessed the role of Kupffer cells in hepLal-/- mice. Depletion of Kupffer cells in hepLal-/- mice had a minor impact on liver inflammation, but it worsened liver cholesteryl ester accumulation and plasma lipids. Because the depletion of Kupffer cells did not improve the hepLal-/- mice phenotype, macrophage depletion is not useful for reducing inflammation in LAL-D livers. Thus, I investigated the modulation of liver inflammation by treatment with the pan-peroxisome proliferator-activated receptor agonist lanifibranor as a potential approach to improve the phenotype of Lal-/- mice. Lanifibranor treatment reduced liver inflammation and improved plasma lipoprotein profile. Hence, lanifibranor treatment might be used as a supplemental treatment to enzyme replacement therapy in LAL-D patients.