The shift in nutrition and lifestyle, which has happened since the industrial revolution, has led to global epidemics in obesity, type 2 diabetes, and cardiovascular diseases. Lipids in the blood are connected to all three conditions.
Medical research has focused on the metabolism of sugar and cholesterol, whereas the fat of triglycerides, the major dietary lipid, has received less attention. The enzyme lipoprotein lipase, LPL, is the cornerstone in blood triglyceride metabolism. This means that LPL must be tightly regulated in response to the nutritional state of the body, and to the needs of particular tissues. LPL is regulated by two groups of proteins – plasma apolipoproteins, which serve as activators or inhibitors of LPL, and angiopoietin-like proteins, which irreversibly inactivate LPL in tissues where triglycerides should not be taken up.
The aim of the thesis was to study the effects of the recently discovered most potent LPL regulators – the angiopoietin-like proteins – on the structure and activity of LPL. Another aim was to develop and validate a novel method to measure LPL activity directly in samples of human plasma.
It was observed that the angiopoietin-like proteins that are capable of acting on LPL use the same mechanism. This involves binding to LPL followed by irreversible unfolding of the active enzyme protein, and, ultimately, dissociation of the LPL dimers to inactive monomers. Oleg Kovrov and the research group studied the complexes formed between various angiopoietin-like proteins and their ability to inactivate LPL. In addition, they have developed a novel method for the measurement of LPL activity directly on natural lipoproteins in plasma samples. This method offers multiple advantages over existing techniques. This method was later applied in a study of plasma samples from a group of essentially healthy individuals. Interestingly. I was observed that most of the known LPL regulators in plasma had a limited effect on the recorded LPL activity. Other variables, like the size of the lipoproteins, seemed to play a more important role.
The study is based on the biochemical and biophysical experiments. This allowed us to evaluate the role of different LPL regulators and to determine the molecular mechanisms they use to regulate blood triglyceride metabolism. Additionally, we studied plasma samples from the VIPVIZA project, initiated in the NUS, Umeå, in order to understand the disturbances in plasma lipids handling in patients.
Oleg Kovrov has previously done Bachelor studies at Tallinn University of Technology, Estonia.
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About the public defense of the doctoral thesis
Oleg Kovrov, Department of Medical Biosciences, 13 June at 9.00 defends his doctoral thesis Regulation of Lipoprotein Lipase Activity: an In-vitro Study of a Complex and Dynamic System. Faculty opponent Geesje Dallinga -Thie, PhD; Senior Research Associate; Departments of Vascular and Experimental Vascular Medicine, Vrije Universiteit, Amsterdam. Principal supervisor Gunilla Olivecrona. Location: Lecture hall D, Unod, 9th floor, University Hospital, Umeå.