Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Vujic, N.
Atherosclerosis susceptibility of mice deficient in enzymes involved in lipolysis and lipogenesis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] ; 2015. pp.
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- Autor*innen der Med Uni Graz:
- Vujic Nemanja
- Betreuer*innen:
- Kratky Dagmar
- Altmetrics:
- Abstract:
- Macrophage-derived foam cells represent the main core of the atherosclerotic plaque and thus largely contribute to lesion dynamics. Enzymes regulating lipid metabolism in macrophages have been poorly investigated in the past. However, they strongly regulate macrophage function and concomitantly affect the process of atherogenesis. In the first part of this thesis, I investigated the role of monoglyceride lipase (MGL) as the final enzyme in lipolysis on macrophage function, lipid and carbohydrate metabolism, and atherosclerosis development. Therefore, I generated atherosclerotic MGL/Apolipoprotein E double knockout (DKO) mice. Since MGL cleaves 2-arachidonoylglycerol (2-AG), the main endocannabinoid in mammals, it also affects a wide range of functions involved in lipid metabolism and inflammatory responses. I found systemically elevated 2-AG levels as well as increased aortic and hepatic 2-AG concentrations in DKO mice. Additionally, DKO mice had reduced systemic inflammation, delayed chylomicron secretion, decreased hepatic steatosis, increased cholesterol elimination via stool, and improved carbohydrate metabolism, which all may affect atherosclerosis progression. Interestingly, DKO animals developed increased atherosclerotic plaques, but these lesions were anti-inflammatory with reduced macrophage and lipid accumulation, decreased necrotic core size, and enlarged collagen-rich fibrous cap, which protects the lesion and prevents its rupture. The results obtained from DKO mice clearly demonstrate a range of metabolic and inflammatory parameters, including the atherosclerotic phenotype, which are improved due to MGL deficiency. Thus, pharmacological inhibition of MGL emerges as a potential target for treatment of metabolic disorders. In the second part of my thesis, I investigated the relative contribution of DGAT1 deficiency in hematopoietic cells and the concomitant effect on atherosclerosis development. Previous research showed that DGAT1/ApoE-DKO mice have reduced atherosclerotic plaque formation. The reduction in plaque size can be attributed either to reduced foam cell formation and ameliorated macrophage response to inflammation or to reduced intestinal cholesterol uptake and absorption, which resulted in reduced plasma lipid concentrations. To determine solely macrophage contribution to the observed effect, we transplanted low-density lipoprotein receptor-KO mice with the bone marrow from wild-type or DGAT1-KO mice. We found comparable plaque formation in both genotypes with the development of unfavorable, destabilizing lesion profile in DGAT1-/- transplanted mice, due to increased plaque macrophage and reduced collagen content. These data clearly indicate that hematopoietic DGAT1 deficiency does not cause the improved atherosclerosis observed in DGAT1/ApoE-DKO mice, arguing in favor of decreased plaque formation due to altered cholesterol lipid metabolism in these animals.