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Selected Publication:
Schinagl, M.
Lipid Hydrolysis in Liver Disease
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 113
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- Authors Med Uni Graz:
- Advisor:
- Birner-Grünberger Ruth
- Hämmerle Guenter
- Trauner Michael
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- Abstract:
- Liver cancer is one of the few types of cancer with rising levels of occurrence. This is mostly due to growing levels of obesity and the subsequent increase in non-alcoholic fatty liver dis-ease initiating development of liver fibrosis and cancer. In this thesis we explore abnormal lipid metabolism in liver cells and its consequences on cell proliferation, glucose metabolism, and fibrotic potential of specialized liver cells (hepatic stellate cells). For this, we take a closer look at three important proteins in liver lipid metabolism using phenotypic and proteomic analyses. First, we show that a decrease of the major triglyceride catabolizing protein activity Adipose-triglyceride-lipase (ATGL) merely increases cytosolic lipid droplet volume, but does not influence cell growth, despite ATGL showing decreased expression in liver cancer cells, compared to healthy tissue. The upstream regulator of ATGL, CGI-58 (ABHD5), displays similar downregulation in liver cancer tissue as ATGL, compared to healthy tissue. CGI-58 silencing likewise increased cytosolic lipid droplet volume, but also positively affected cell growth in hepatocytes. Proteomic and phenotype analysis of CGI-58 depleted hepatocytes indicated a switch to increased glycolysis, resembling a shift towards a more cancerous phenotype in these cells. Interestingly, an overabundance of CGI-58 did not cause any of the above-mentioned metabolic changes in the hepatocyte phenotype. Next, we found that PNPLA3, an enzyme associated with an increase in liver disease in its mutated form, showed similar effects to CGI-58 downregulation on alterations of lipid and glucose metabolism. Second, we investigated the proteome and phenotype of specialized liver cells, so called hepatic stellate cells (HSC). These cells are responsible for initiating fibrosis in the injured liver and undergo massive changes during their transformation from a resting “quiescent” state, into an “active” fibrotic state. We demonstrate that this activation is associated with an in-crease in migratory behaviour, increased proliferation, lipid droplet volume loss, an increase in protein production, and a switch towards a glucose-focused metabolism. Moreover, in-creased I148M PNPLA3 mutant expression (a common mutation in humans) in these cells was accompanied by an upregulation of proteins strongly associated with cancer aggressive-ness. Collectively, we demonstrate the importance of functional lipid metabolism in liver cells and show how lipid metabolism is connected to other energy metabolism pathways.