Finansår , 2003, 2004, 2005, 2006, 2007
huvudman: T. Olivecrona, finansiar: VR-M, y2003: 300, y2004: 325, y2005: 325, y2006: 275, y2007: 275,
The major step in metabolism of triglyceride (TG) rich lipoproteins, and in delivery of their fatty acids to tissues, is hydrolysis of the TG by lipoprotein lipase (LPL). This occurs while the lipoprotein is anchored to a “binding-lipolysis site” at the vascular endothelium. Our research explores some aspects of the events at such sites. Experiments are carried out with whole animals (mainly rats and mice, both wild type and genetically modified), in perfused tissues (heart, adipose tissue, liver) and organ culture (adipose tissue). Major questions asked concern:
- How do TG-rich lipoproteins bind to the endothelium and establish contact with the lipase?
- What is the residence time for the lipoprotein particle at such a “binding-lipolysis site”. Is this the same in different tissues and under different conditions, e.g. the fed and the fasted state?
- Are all the functional lipase molecules at the luminal surface of the endothelium or is there continuous movement of lipase to/from other sites in the tissue?
- Are there pathways by which lipase at the endothelium can re-enter the tissue and be degraded?
- What is the quantitative contribution of local degradation and of transport to the liver for turnover of LPL in different tissues?
- Does heparin wash out the tissue stores of LPL and what are the consequences for lipoprotein metabolism?
- What is the molecular mechanism for down-regulation of LPL activity in adipose tissue between meals? Do similar mechanisms operate in other tissues as well? What signals and signal transduction pathways are involved?