As described in a former post, part of the IDL is not captured by the hepatocyte, but continues in plasma losing TAG and increasing its Cholesterol content, becoming Low Density Lipoproteins or LDL.
The lipid core of LDL is formed mainly by cholesterol esters:
The only apoprotein that is present at the LDL surface is Apo B-100.
Due to the structural changes that occur during the conversion of VLDL to IDL and from IDL to LDL, Apo B expose a domain that can interact with LDL receptors (receptors for Apo B-100) that are located in the liver but also in extrahepatic tissues.
The binding of LDL and the receptor in the hepatocyte surface triggers an endocytosis process (“receptor-mediated-endocytosis”), with the formation of endosomes. Changes in Ph provoke the dissociation between the lipoprotein and the receptor, the receptor returns to the membrane while the endosome fuse with a lysosome; lysosome enzymes hydrolyze the LDL proteins, the cholesterol esters and other lipids.
An excellent animation about receptor-mediated endocytosis can be found here:
The cholesterol, fatty acids and amino acids released from the LDL hydrolysis can be used in cell metabolism. Cholesterol can be used for the synthesis of membranes or it can be reesterified for storage, in a reaction catalyzed by the Acyl CoA Cholesterol Acyl Transferase (ACAT).
Analyzing the process of transformation of the lipoproteins, it is seen that the lipids synthesized by the liver, or that arrive to it through the Chylomicrons remnants, are redistributed to the extrahepatic tissues through the VLDL-IDL-LDL system: VLDL provide to these tissues neutral fats, IDL are transitional lipoproteins that can supply TAG/Cholesterol, and LDL endow the extrahepatic tissues with Cholesterol formed in the liver, the main organ that synthesize cholesterol.
The signal that a cell needs cholesterol is expressed through the presence of LDL receptors in the cell surface: the synthesis of LDL receptors is inhibited by high intracellular concentrations of cholesterol.
Since high intracellular concentrations of Cholesterol inhibit the synthesis of LDL receptors, there is a decrease in the take over of plasmatic cholesterol that forms the LDL. This LDL Cholesterol (LDLc) can be deposited in some tissues, including arteries and provoking arteriosclerosis.
Statin drugs decrease plasmatic cholesterol because they inhibit the activity of HMGCoA reductase, and consequently, cholesterol synthesis, decreasing the intracellular concentration of Cholesterol. It provokes an increase in the synthesis of LDL receptors, and therefore, a higher intake of LDL by the cell and a decrease of cholesterolemia.
Treatments for Hypercholesterolemia pay great attention to control the LDL-Cholesterol
Any disruption in the delicate mechanism that regulates cholesterol metabolism may provoke alterations in the plasmatic and intracellular Cholesterol concentration.
Familial Hypercholesterolemia, aka Hyperlipidemia Type II, is an autosomal dominant genetic disease, which is consequence of defects in LDL receptors. This is the most frequent cause of Hyperlipidemia in the general population (in the United States, about 1:500) and is characterized by xanthomas in
Achilles’ tendon, and hand tendons, a marked elevation of LDL cholesterol, slow clearance of cholesterol, (but TAG and HDL in normal range), and arteriosclerosis signs. Homozygotes usually suffer from heart attack very young.
A lot less frequent, a defect in the structure of Apo B-100 (Familial Ligand Defective Apo B-100) can provoke a very similar condition, since in this case there are functional LDL receptors, but structural alterations in this Apolipoprotein B does not allow the recognition and binding.
In the opposite range, it is possible to find a condition characterized by the lack of LDL, plasmatic Chylomicrons and VLDL. It occurs because of a congenital deficit of the synthesis of Apo B. This kind of defect is classified as a Hypolipoproteinemia.
For additional information:
Low Density Lipoproteins