Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Duta-Mare, M.
Role of lysosomal acid lipase in thermogenesis and energy homeostasis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2018. pp. 118
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kratky Dagmar
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- Abstract:
- Obesity, diabetes mellitus, atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and their downstream morbidities are the most common causes of mortality in the modern society. Although weight loss and exercise have a beneficial impact on the prevention and cure of these diseases, very little is done in this direction by and for the patients. Thus, many efforts are directed toward pharmacological targeting of different components of the metabolic syndrome, such as dyslipidemia, fat mass, hypertension, hyperglycemia, etc. Lysosomal acid lipase (LAL) is a critical cholesteryl ester (CE) and triglyceride (TG) hydrolase and it is widely expressed in most cell types. LAL deficiency (LAL-D) in humans and mice produces a bulk of complications, which converge to premature demise. Hallmarks of LAL-D are excessive accumulation of neutral lipids in liver, intestine and lungs, resulting in dyslipidemia and severe immune imbalance. To date, the most studied aspects are cholesterol accumulation in liver and the inflammatory angle, but still little is known about energy metabolism in the absence of the main lipase involved in lipoprotein catabolism and lipid autophagy. LAL-D is often misdiagnosed and is categorized as a morbidity of the metabolic syndrome in adults, due to fatty liver and atherosclerosis, but these patients are rarely overweight. Moreover, LAL-D infants/children and animal models of the disease are cachectic. This thesis targets mainly the physio/pathological role of LAL in thermogenesis and energy metabolism with the aim of revealing potential therapeutic targets in the battle against obesity and cardiovascular disease. In the first part of the thesis, we focused on investigating the role of LAL in thermogenesis, using the LAL-deficient (Lal-/-) mouse model with the aim of dissecting the relationship between acid and neutral lipid hydrolysis in fueling brown adipose tissue (BAT). We provide evidence that LAL deficiency produces a metabolic imbalance in mice and thus affects whole body energy metabolism and overall thermogenesis. In the second and third part, comparing mice with total and tissue-targeted LAL deletion (adipose tissue, atLal-/- and macrophages, macLal-/-), we studied the distinct role of LAL in different cell types in connection to its global contribution to lipid and carbohydrate metabolism. We found that adipose tissue LAL is important for buffering fatty acids (FA) demand during fasting, but not during cold exposure. Except for minimal effects, tissue-specific LAL deficiency does not fundamentally affect energy metabolism in mice challenged with diet rich in fat and cholesterol. Our data help to understand the distinct roles of LAL in pathological conditions. While the molecular aspects of these metabolic adaptations in cells lacking LAL remain to be addressed, this study revealed the critical impact of LAL on energy metabolism and thermogenesis. Since BAT activity in humans is positively correlated with metabolic health, it is plausible that defective BAT function additionally aggravates dyslipidemia in LAL-D patients.