Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Korbelius, M.
Consequences of intestinal CGI-58/ATGL deficiency and ATGL overexpression on gut lipid homeostasis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 135
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- Autor*innen der Med Uni Graz:
- Korbelius Melanie
- Betreuer*innen:
- Kratky Dagmar
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- Abstract:
- Systemic lipid levels are mainly determined by dietary lipid absorption and lipoprotein secretion by enterocytes of the small intestine (SI) as well as by rapid chylomicron (CM) clearance by the liver. Excessive triglycerides (TGs), originating from apical (diet) or basolateral (circulation) lipid uptake, are transiently stored in form of cytosolic lipid droplets (cLDs). Mobilization of this intracellular lipid pool is believed to sustain peripheral lipid supply in interprandial periods, however, the underlying mechanism(s) and enzyme(s) involved are still elusive. As mice lacking adipose TG lipase (ATGL) in the gut displayed massive accumulation of cLDs, we hypothesize that the enzymatic pathway accountable for the catabolism of intestinal cLDs involves ATGL and its coactivator comparative gene identification-58 (CGI-58). To prevent systemic effects of CGI-58/ATGL deficiency, we generated mice lacking both proteins exclusively in the SI (Cgi-58/Atgl iDKO). Loss of intestinal CGI-58/ATGL resulted in increased cLD accumulation within enterocytes, independent of the diet. Alimentary lipids failed to accumulate in the SI of iDKO mice in the early phase of absorption, but got incorporated into cLDs 2 h post-gavage. These findings together with persistent cLD accumulation after restriction to endogenous lipids indicated the existence of a secretion/reuptake cycle in enterocytes. In line, accumulation of intravenously applied lipids in the proximal SI of iDKO mice highlighted the role of intestinal CGI-58/ATGL in the hydrolysis of a basolaterally-derived lipid pool. To further investigate the contribution of solely ATGL to intestinal and whole-body lipid homeostasis, we also generated mice overexpressing ATGL (Atgl iTg) specifically in the SI. Previous studies in Atgl iKO mice revealed a role of ATGL in cholesterol absorption rather than in dietary TG metabolism. In line, Atgl iTg mice displayed accelerated cholesterol absorption, which was mainly mediated by the activation of PPARα. Although Atgl iTg mice displayed slightly impaired secretion of CM-TGs and –cholesterol, ATGL seems to play a neglible role in intestinal lipoprotein metabolism. Both studies demonstrated that lipid hydolysis in the SI is by far more complex than described in previous models, highlighting the necessity to modify the current model of intestinal lipid metabolism. We could identify CGI-58 and ATGL as critical players in the catabolism of a basolaterally-derived intestinal lipid storage pool rather than alimentary lipids. However, the enzyme responsible for the catabolism of dietary lipids still remains elusive. Identification of potential lipid hydrolases in the SI and future studies in this field should lead to the identification of new drug targets to treat elevated lipid levels in blood and intestine.