Cholesterol Schematic

HDL particles can be distinguished into discoidal (disk-shaped) and spherical ones. The discoidal ones are termed nascent (n-HDL), the spherical ones mature HDL particles. Plasma contains mostly spherical particles with a hydrophilic core, consisting of triglycerides and cholesterol esters surrounded by phospholipids and apoproteins. The transition of the nascent to the spherical form is a result of cholesterol esteri-fication and uptake of cholesterol esters from the surroundings.

Inside the plasma, n-HDL (A), which is secreted by the liver, encounters the enzyme lecithin cholesterol acyl-trans-ferase (LCAT), which catalyzes the esterification of cholesterol in the n-HDL's core. The resulting HDL-3 continues to take up cholesterol and cholesterol esters. Additionally, an intensive exchange takes place between chylomicrons (CM) and VLDL. The additional ApoA required comes from a pool of free ApoA that results from breakdown of the CM surface. Peripheral cell receptors recognize this ApoA on the surface of HDL particles and trigger the release of intracellular cholesterol to them. This continuous process of cholesterol uptake, cholesterol esterification through LCAT, and modification of the apoprotein surface particles results in the formation of HDL-2 and HDL-1. These may, on the one hand, be taken up and metabolized by hepatocytes, either through receptors, or through receptor-independent mechanisms. On the other hand, they may also yield just parts of the lipophilic core and subsequently parts of the surface, converting them back into their respective precursor stages. Through this continuous cycle, HDL fulfills its essential function: the transport of cholesterol and triglycerides back from the peripheral tissues to the liver, where they are converted primarily into bile acids.

It is not yet fully understood how HDL particles remove cholesterol from cells. For monocytes (macrophages), trans-cellular transport of the HDL-HDL receptor vesicle has been proposed, during which HDL gets enriched by cholesterol from lipid droplets (B). Other theories assume the binding of HDL-ApoA to a receptor and subsequent (unexplained) permeation of intracellu-lar cholesterol into the HDL. Since various apoproteins themselves can serve as cholesterol acceptors, even an uptake of ApoA, e. g., into cells and subsequent intracellular formation of pre-HDL (n-HDL) might be possible.

Transfer proteins (active in the plasma) may play important roles in regulating lipoprotein metabolism, for instance, when controlling the efflux of cholesterol from peripheral cells. Besides cholesterol ester transfer protein (CETP), which enables the exchange and net transfer of cholesterol esters (CE), triglycerides (TG) and phospholipids (PL), there is a phospholipid transfer protein (PTP), which is limited to transporting PL and TG. This way, TG and CE may be swapped between HDL and triglyceride-rich particles such as chylomicrons or VLDL.

Diagram Cholesterol Pathophysiology
B. Cholesterol Uptake in Monocytes/Macrophages

Cholesterol

EC Lipid droplet

Binding

Cholesterol

EC Lipid droplet

Lipoprotein Metabolism
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