The VLDL undergoes modifications and transforms into LDL in the plasma. This conversion process also leads to the formation of intermediate-density lipoproteins (IDL) of different sizes. Liver cells can take up IDL through receptor-mediated endocytosis, which involves apo E as the ligand. Apo E exists in three isoforms: E-2 (least common), E-3 (most common), and E-4. Apo E-2 has poor binding with receptors, causing deficient clearance of IDL and chylomicron remnants in individuals homozygous for apo E-2. These individuals suffer from familial type III hyperlipoproteinemia, which leads to hypercholesterolemia and premature atherosclerosis. The apo E-4 isoform increases susceptibility to an earlier onset of late-onset Alzheimer's disease, with the risk being highest in homozygotes.

LDL particles contain less TAG compared to VLDL and have a high concentration of cholesterol and cholesteryl esters. Approximately 70% of plasma cholesterol is found in LDL. The main role of LDL particles is to provide cholesterol to peripheral tissues or return it to the liver. They accomplish this by binding to plasma membrane LDL receptors that recognize apo B-100 (but not apo B-48). These receptors are referred to as apo B-100/apo E receptors since they can also bind apo E. The uptake and degradation of LDL particles, as well as chylomicron remnants and IDL by the liver, follow a similar mechanism of receptor-mediated endocytosis.

LDL receptors are negatively charged glycoproteins clustered in pits on cell membranes. The cytosolic side of the pit is coated with the protein clathrin, which stabilizes it. Once bound, the LDL-receptor complex is endocytosed. Defects in the synthesis of functional LDL receptors result in significantly elevated plasma LDL-C levels. This condition is known as type IIa hyperlipidemia or familial hypercholesterolemia (FH) and leads to premature atherosclerosis. Autosomal dominant hypercholesterolemia can also occur due to defects in apo B-100, reducing its binding to the receptor, or increased activity of the protease PCSK9, which promotes internalization and lysosomal degradation of the receptor. PCSK9 inhibitors are now available for the treatment of hypercholesterolemia.

The vesicle containing LDL loses its clathrin coat after endocytosis and merges with other similar vesicles, forming larger vesicles called endosomes. The pH of the endosome decreases due to the proton-pumping activity of endosomal ATPase, causing separation of the LDL from its receptor. The receptors then migrate to one side of the endosome, while the LDL remains free within the lumen of the vesicle.
3. Conversion to low-density lipoproteins: With these modifications, the VLDL is converted in the plasma to LDL. Intermediate-density lipoproteins (IDL) of varying sizes are formed during this transition. IDL can also be taken up by liver cells through receptor-mediated endocytosis that uses apo E as the ligand. Apo E is normally present in three isoforms, E-2 (the least common), E-3 (the most common), and E-4. Apo E-2 binds poorly to receptors, and patients who are homozygotic for apo E-2 are deficient in the clearance of IDL and chylomicron remnants. These individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia or broad beta disease), with hypercholesterolemia and premature atherosclerosis. [Note: The apo E-4 isoform confers increased susceptibility to an earlier age of onset of the late-onset form of Alzheimer disease. The effect is dose dependent, with homozygotes being at greatest risk. Estimates of the risk vary.]
D. Low-density lipoprotein metabolism
LDL particles contain much less TAG than their VLDL predecessors and have a high concentration of cholesterol and cholesteryl esters (Fig. 18.19). About 70% of plasma cholesterol is in LDL.
1. Receptor-mediated endocytosis: The primary function of LDL particles is to provide cholesterol to the peripheral tissues (or return it to the liver). They do so by binding to plasma membrane LDL receptors that recognize apo B-100 (but not apo B-48). Because these LDL receptors can also bind apo E, they are known as apo B-100/apo E receptors. A summary of the uptake and degradation of LDL particles is presented in Figure 18.20. [Note: The numbers in brackets below refer to corresponding numbers on that figure.] A similar mechanism of receptor-mediated endocytosis is used for the uptake and degradation of chylomicron remnants and IDL by the liver.
[1] LDL receptors are negatively charged glycoproteins that are clustered in pits on cell membranes. The cytosolic side of the pit is coated with the protein clathrin, which stabilizes the pit.
[2] After binding, the LDL–receptor complex is endocytosed. [Note: Defects in the synthesis of functional LDL receptors causes a significant elevation in plasma LDL-C. Patients with such deficiencies have type IIa hyperlipidemia (familial hypercholesterolemia [FH]) and premature atherosclerosis. Autosomal dominant hypercholesterolemia can also be caused by defects in apo B-100 that reduce its binding to the receptor and by increased activity of a protease, proprotein convertase subtilisin/kexin type 9 (PCSK9), which promotes internalization and lysosomal degradation of the receptor. PCSK9 inhibitors are now available for the treatment of hypercholesterolemia.] [3] The vesicle containing LDL loses its clathrin coat and fuses with other similar vesicles, forming larger vesicles called endosomes.
[4] The pH of the endosome falls (due to the proton-pumping activity of endosomal ATPase), which allows separation of the LDL from its receptor. The receptors then migrate to one side of the endosome, whereas the LDL stay free within the lumen of the vesicle.