SEC of all terrestrial vertebrates

SEC of all terrestrial vertebrates (amphibia, reptiles, birds and mammalia) are located in the liver sinusoids, making up the very lining of these hepatic vessels. In the lower vertebrates salmon and cod the linings of kidney sinusoids and heart endocardium, respectively, but not liver, are made up of SEC. Without respect to anatomical localization, the vertebrate SEC carry out the very important function of ridding the blood of waste macromolecules and colloids. To this end the cells are equipped with 4 or 5 types of endocytosis receptors (hyaluronan receptor, mannose receptor, collagen alpha chain receptor, scavenger receptor, and IgG Fc receptor (only in mammalia). The cells carry out receptor-mediated endocytosis at a higher speed and with higher capacity than most other cells of the body. Since the general function of these cells represents a major axis of research interest of our department several projects deal with receptor-mediated endocytosis of various waste macromolecules, and their subsequent degradation in SEC. Topics that are currently under investigation include: Purification and cloning of special scavenger-, collagen alpha chain- and hyaluronan receptors for endocytosis of a variety of waste products; regulation of intracellular transport of endocytosed ligands to early and late endosomes, and finally to lysosomes; recruitment of lysosomal enzymes via the mannose- and mannose-6-phosphate receptors; degradative capacity; transformation of endocytosed macromolecules to lactate and acetate that may serve as “high octane fuel” for neighbouring high energy consuming parenchymal cells.
Since SEC eliminate circulating waste macromolecules that may start the development of atherosclerosis if they are allowed to accumulate in the blood, the cells are believed to play a very important role in the anti-atherosclerotic defence system. Low density lipoprotein (LDL), a major blood carrier of cholesterol, may be subjected to oxidative modification. In this form (OxLDL) it is recognized by the scavenger receptor, which is expressed by a number of cell types, most notably macrophages and other cells of the intima of large arteries such as aorta, carotis and coronary vessels. Accumulation of OxLDL in these cells may initiate an inflammatory process that develops further to atherosclerosis, including hardening and narrowing of the vessel, which, if allowed to proceed, will trigger platelet activation and blood coagulation, leading ultimately to formation of a thrombus and infarction. In addition to OxLDL, macromolecules modified by advanced glycation (AGE-products), have been shown to cause the development of atherosclerotic plaques. Interestingly, AGE-products are recognized by scavenger receptors in both macrophages and SEC. Thus, the strongly atherogenic molecules AGE and OxLDL are both ligands for the scavenger receptors. A line of research that is currently followed in our department is based on the hypothesis that reduced uptake capacity or increased elimination burdon on SEC scavenger receptor may allow atherogenic substances to escape uptake in liver, which will result in a gradually increased blood concentration of atherogenic substances, among them OxLDL and AGE-products. Activation of platelets will result in the generation of ligands for the scavenger receptor. Serum, which is the result of massive platelet activation, contains large amounts of ligands for the scavenger receptor. These ligands effectively compete with test ligands for uptake via the scavenger receptor. We are currently carrying out and designing experiments to test the hypothesis that the abnormally easily activatable platelets in diabetics may be one mechanism that contributes to the increased incidence of atherosclerosis and other serious vascular complications frequently seen in diabetes. We likewise perform experiments to test whether the diabetic atherosclerosis model can explain the mechanism of increased incidence of atherosclerosis in old people.