Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Gindlhuber, J.
Fatty acid species-dependent hepatic cellular lipotoxicity
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 104
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Birner-Grünberger Ruth
- Malli Roland
- Altmetrics:
- Abstract:
- Non-alcoholic fatty liver disease (NAFLD) is a ubiquitous condition affecting, on average, one out of four people throughout their adult life. Accurate numbers are hard to determine as only specialized diagnostic methods, like magnet resonance imaging, can detect elevated lipid content in the liver. Early stages of NAFLD most often not being accompanied by inflammation or other easily measured biomarkers and the disease occurs transiently. All of these facts belittle the reality that the majority of cryptic cirrhosis cases might originate from this seemingly mild alteration of the liver’s metabolic state, becoming chronic. At a certain point, following an initial accumulation of lipids in the liver originating from either overabundant food intake or release from the adipose tissue, alteration in the hepatocytes’ morphology and physiology can be encountered. These alterations go hand in hand with mild lobular inflammation in the beginning and fibroblast recruitment, progressing over time into severe scarification due to increased fibrin deposition in the tissue and ending with the loss of liver function, at this point termed cirrhosis. At this final stage, the only possible treatment is a liver transplant, whilst a change in lifestyle could have likely prevented any further progression at an earlier stage. Thus, key to improving our understanding of hepatic lipotoxicity is resolving these first steps of hepatocyte alteration which occurs when the liver is seemingly still healthy, before inflammation and irreversible fibrosis takes place. This study focused on investigating alterations introduced to hepatocytes with artificial shifts in abundance of individual and mixed fatty acids in the medium. We employed high resolution mass spectrometry approaches to investigate proteome and lipidome of cultured hepatocytes as well as microscopy and flow cytometry techniques to examine their phenotypical and physiological changes. Results from this study suggest that despite the fatty acid treatment causing major changes to the proteome, only a few of them are unique for lipotoxic fatty acids concentrations. In addition, we were able to identify ectopic accumulation diglycerides and ceramides previously described to cause lipotoxic effects in other tissues. Finally, we were able to show for the first time that different long chained fatty acids can influence the cellular fate in divergent ways within the same cell system.