HDL in inflammation and diabetes
The role of high-density lipoprotein (HDL) in the reverse cholesterol transport pathway where excessive, and thus harmful, cholesterol is transported for secretion is well established. Additional functions of HDL include attenuation of endothelial inflammation and improved glucose metabolism in the diabetic state. Learning more about the specific influences of different species of HDL on these beneficiary processes, and how the interaction with the cell surfaces and the intracellular signaling and regulation may occur, will lead us in the search for new ways to prevent and treat type 2 diabetes and atherosclerosis.
Spatial and temporal distribution of glucose transporters
In adipose and muscle cells, glucose transport is facilitated by the insulin responsive glucose transporter protein GLUT4. In adipose cells, under non-stimulated conditions, the major part of GLUT4 is stored in intracellular glucose storage vesicles (GSV). Insulin stimulation promotes tethering and fusion of GSV with the plasma membrane, thereby increasing the amount of transporter in the membrane that facilitates glucose diffusion into the cell and hence lowers the blood glucose level. Even though many of the mediators downstream of the insulin receptor like PI3-kinase and protein kinase B (PKB) involved in regulation and trafficking of GLUT4 are known, great effort is spent in order to elucidate the regulatory mechanism of the last fusion step, which is proposed to be the critical insulin-regulated step.
In muscle, also contraction induces GLUT4 translocation but far less is known about the signal pathway and mediators involved; much due to the complex morphology of muscle cells. We make use of a transgenic mouse model with muscle-specific expression of HA-GLUT4-GFP to elucidate the regulation and dynamic arrangement of GLUT4 in live cells using different microscopy techniques. Understanding the regulatory mechanisms of both insulin and contraction induced glucose uptake is fundamental in order to find treatments and prevent type 2 diabetes.
Structure dynamics of apolipoprotein A-I in HDL
Apolipoprotein A-I is the major protein component of high-density lipoprotein (HDL) and thus important in the transportation of cholesterol and other lipids between tissues in vivo. To accommodate a variation in type and amount of lipids the apoA-I structure switches between several conformational states. These states include the relatively compact lipid-free/poor structures, the more expanded and disc-shaped pre-beta-HDL particles (or nanodiscs), and matured spherical complexes. In addition, several variants of apoA-I are known to aggregate as amyloids in vivo leading to organ dysfunction. Knowing about the molecular details of these intermediates and the transitional processes will allow for mechanistic understanding of the atheroprotective function of normal and mutated apoA-I.
Molecular structures of Zinc transporter ZnT8 in type 1 and 2 diabetes
The ZnT8 transporter is located in the phospholipid bilayer membrane of insulin granule in pancreatic beta-cells where it facilitates transport of zinc ions from the cytoplasm into the granular lumen. Sufficient levels of zinc in the granular lumen are needed for controlled aggregation of insulin peptides into stable hexameric organizations. A functional ZnT8 structure that ensures Zn2+-influx is thus of great important. Structural and functional analyses are used to clarify molecular constrains related to the contribution of the ZnT8 protein in beta-cell dysfunction associated with type 2 diabetes. (Collaboration with the research groups of Karin Lindkvist and Åke Lernmark)