STK25 A new regulator of the risk of metabolic liver disease and cardiovascular disease risk
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Examensarbete för masterexamen
Master Thesis
Master Thesis
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Modellbyggare
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Sammanfattning
Cardiovascular diseases (CVDs) are today the leading cause of death, accounting for 31% of all deaths globally. Recently, attention has focused on the importance of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in the development and progression of CVDs. Recent studies, by the research group of Assoc. Prof. Margit Mahlapuu, Gothenburg University, have identified serine/threonine kinase 25 (STK25), a protein belonging to the sterile 20 kinase superfamily, as a key regulator of liver lipid metabolism, whole-body glucose and insulin homeostasis, and the progression of NAFLD/NASH, based on results from well-characterized patient populations, cultured human cells and unique mouse models. The aim of this project proposal is to elucidate the integrated molecular mechanisms linking NAFLD/NASH to CVD, with the focus on the novel mediator STK25. Importantly, the study has a potential to lay a scientific basis to reduce CVD risks and to find novel therapeutic strategies for its treatment. The role of STK25 in the plaque progression of atherosclerosis was studied using Stk25 transgenic (TG) and knockout (KO) mice with low-density lipoprotein receptor (LDLR) deficiency induced through a single injection of recombinant adeno-associated virus (rAAV) encoding gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (PCSK9), combined with an atherogenic western-type diet. The plaque maturation and lesion area were evaluated by histological studies in aortic root sections together with measurements of NASH progression in liver samples. Stk25 TG mice displayed an increase in lesion area, plaque maturation, inflammatory response as well as more advanced NASH, compared to their corresponding wildtype (WT) littermates. Reciprocally, Stk25 KO mice demonstrated decreased plaque formation, aggravated lesions and less signs of NASH, compared to their corresponding WT littermates. The results of this project provide evidence that STK25 plays an important part in the progression of atherosclerosis due to excess dietary intake. Further studies are needed to understand the upstream regulators, and the downstream targets, in the signalling pathway of STK25.
Beskrivning
Ämne/nyckelord
Livsvetenskaper, Cell- och molekylärbiologi, Cellbiologi, Medicinsk bioteknologi, Life Science, Cell and molecular biology, Cell Biology, Medical Biotechnology