Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Kuppusamy Palaniappan, T.
Studies on the Role of Lipoprotein Lipase Mediated Lipotoxicity of Skeletal Muscle and the Effect of Adipose Triglyceride Lipase in the Tumor Metabolism
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 88
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- Autor*innen der Med Uni Graz:
- Kuppusamy Palaniappan Tamilarasan
- Betreuer*innen:
- Höfler Gerald
- Kratky Dagmar
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- Abstract:
- The main energy storage sites of animals are their adipocytes. If fat is stored ectopically, for example in liver, heart, or skeletal muscle it induces pathological changes such as fatty liver, lipid cardiomyopathy, non-insulin dependent diabetes mellitus, and skeletal muscle myopathy. Lipotoxicity is the ectopic accumulation of lipids in non-adipose tissue , which negatively affects cells. It is not clear whether the fat stored ectopically in muscle is lipotoxic. To study direct effects of lipotoxicity in muscle MCK(m)-hLPL mice expressing lipoprotein lipase (LPL) exclusively in skeletal and cardiac muscle, and the C2C12 cell-line overexpressing hLPL were used. The studies showed that ectopic lipid accumulation lead to enhanced apoptosis and proteasomal activity as well as muscle damage as evidenced by loss of physical performance. In addition, morphological changes were observed using electron microscopy. Moreover, the studies indicated a drastic decrease in muscle regeneration, which was also evidenced by a loss of myogenic differentiation in C2C12 murine satellite cells overexpressing hLPL. Lipid metabolism starts with the uptake of lipids in the form of fatty acids by LPL . Later on, lipids are stored as triglyceride in cells. In adipocytes triglycerides are predominantly cleaved by Adipose Tri-Glyceride Lipase (ATGL), which leads to the release of fatty acids. Metabolism of lipids is important to maintain normal cell functions. Altered lipid metabolism results in abnormal cellular function. Increasing evidence indicates that cancer cells show alterations in different aspects of lipid metabolism. There are inhibitors like SB-204990, acetyl-coA carboxylase (ACC) inhibitors, and fatty acid synthase (FAS) inhibitors targeting the lipid metabolism that are emerging as anticancer strategies. However, the role of ATGL in the course of malignant diseases is unclear. To explore the role of ATGL in tumors, wild type (Wt) and syngeneic ATGL knockout (ATGL-ko) tumor cells were created by transducing p185bcr-abl in B-cells derived from bone marrow of Wt and ATGL-ko mice, respectively. In addition, ATGL of Lewis lung carcinoma cells (LLC) was permanently inhibited by stable expression of pre-miRNA which could target ATGL. The growth characteristics of ATGL-ko cells and Wt cells were studied in vitro as well as in vivo. ATGL-ko B-cells showed growth characteristics similar to Wt cells when cultured in vitro. When injected into mice and analyzed for tumor growth, Atgl-ko cells formed bigger tumors than Wt cells, indicating that ATGL may play a role in the tumor growth. In addition, studies of Atgl-ko cell growth in immune suppressed RAG2–gamma mice and RAG2-mice point to differences in the immunogenicity of Atgl-ko tumor cells. In summary, research related to lipid metabolism with respect to lipotoxicity indicated that skeletal muscle overload of lipids by hLPL caused increased toxicity leading to poor growth of the cells which causes altered physical performance. Research on lipid metabolism related to cancer indicated that the inhibition of ATGL leads to increased tumor growth in mice. Based on these observations I conclude that overload of lipids by hLPL can alter the physiological function according to the concept of lipotoxicity but that ATGL might have other functions in the context of tumor metabolism which have to be studied further.