Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Bianco, V.
Consequences of (intestinal) LAL deficiency on whole body lipid metabolism
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2024. pp.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kratky Dagmar
- Altmetrics:
- Abstract:
- The survival of the whole organism depends on the small intestine (SI), which comprises over 80% of the gastrointestinal system. The SI is involved in the absorption and processing of nutrients, the elimination of toxins, and the defense against pathogens. Duodenum, jejunum, and ileum are the three distinct regions that constitute the SI from the proximal to the distal end, and each part is dedicated to a specific function. As the SI is always in contact with dietary lipids, we suggested that the lysosome and its only known lipase, lysosomal acid lipase (LAL), play an important role in intestinal lipid metabolism. LAL deficiency (LAL-D) results in an accu-mulation of lipids in various organs, mainly in the liver, spleen, and SI. The major symptoms of LAL-D patients are vomiting, diarrhea with steatorrhea, and abdominal distension, which even-tually lead to early death. To elucidate the role of LAL in intestinal metabolism, we generated a mouse model lacking the enzyme exclusively in enterocytes (iLal KO). Although LAL mRNA expression and protein ac-tivity were significantly reduced in iLal KO mice, no obvious phenotype was observed when compared to control, but especially, in respect of global Lal KO mice. On the other hand, we identified a Trem2-like phenotype in lipid-filled macrophages infiltrating the duodenum of Lal KO mice. To increase our knowledge on the mechanisms behind the intestinal phenotype of Lal KO mice, we performed untargeted proteomics on the three separate intestinal parts of these mice. We found that despite a similar Trem2-like signature in macrophages infiltrating the SI, only duodenal macrophages of Lal KO mice activated a metabolic shift toward mitochondria-related pathways. On the other hand, jejunum and ileum displayed an opposite profile by downregu-lating similar pathways. We also identified GPNMB and soluble TREM2 as potential bi-omarkers of LAL-D and its systemic inflammation, respectively. Finally, as the microbiome plays an essential role in regulating host metabolism, we investi-gated whether loss of LAL has an impact on the microbial composition. We found that Lal KO mice display drastic changes, including increased abundance of species formerly associated with lipid-rich environments and a decrease in short chain fatty acid-producing bacteria, and a reduction in a coprostanol-producing strain, which might contribute to the high cholesterol lev-els measured in feces of Lal KO mice.