The ABC of cholesterol transport

Cholesterol fulfills an indispensable role in mammalian physiology. It is an important constituent of all cell membranes. Furthermore, it is the precursor of steroid hormones, which regulate a variety of physiological functions, and of bile salts, which are necessary for the generation of bile flow and the intestinal absorption of lipids and lipophilic vitamins. Cholesterol can be derived from the diet as well as from endogenous synthesis, the latter being the major source in humans. Apart from its vital role in the body, cholesterol also poses a potential threat on human well-being. High plasma cholesterol concentrations, especially in the Low-Density- Lipoprotein (LDL) fraction, are associated with an increased risk for development of atherosclerosis. This is due to its accumulation in macrophages present in blood vessels, representing a key step in the formation of an atherosclerotic plaque. Therefore, it is not surprising that various, tightly regulated pathways exist to eliminate excess cholesterol from the body. The route from peripheral tissues via the liver to the feces has been defined as reverse cholesterol transport. Shortly, at the level of the peripheral cell, cholesterol is excreted via the action of the ATP-binding cassette transporter ABCA1 towards High-Density-Lipoprotein particles (HDL), the so-called “good cholesterol”. The parenchymal cells of the liver (hepatocytes) take up cholesterol from HDL and excrete it into the bile either as free cholesterol or after its conversion into bile salts. Subsequently, cholesterol (or its bacterial metabolites) and bile salts end up in the feces. Different mechanisms exist to maintain cellular cholesterol homeostasis. On the one hand, the expression of enzymes which are involved in cholesterol and bile salt synthesis (liver cells only) is regulated at various levels, controlling both cholesterol synthesis and catabolism. On the other hand, the expression of transport proteins, which promote uptake, trafficking and excretion of cholesterol in the cell, is also tightly regulated. As a consequence cholesterol fluxes within the body are also tightly controlled. Gene expression of the major transporters studied in this thesis is regulated by a transcription factor called Liver-X-Receptor (LXR). This receptor senses the level of oxidized cholesterol derivatives, oxysterols, and thereby indirectly the concentration of cholesterol in the cell. This thesis aims to elucidate the mechanisms involved in cholesterol transport and their molecular regulation by LXR, especially at the level of the enterocyte and the hepatocyte