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.

Figure 1:  Composition of the plasma lipoprotein particles. Note the high concentration of cholesterol and cholesteryl esters 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 2. [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.

Figure 2:  Cellular uptake and degradation of low-density lipoprotein (LDL) particles. [Note: Oversupply of cholesterol accelerates the degradation of HMG CoA reductase. It also decreases transcription of its gene as seen with the LDL receptor.] ACAT = acyl CoA:cholesterol acyltransferase; HMG CoA = hydroxymethylglutaryl coenzyme A; mRNA = messenger RNA.

[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.

[5] The receptors can be recycled, whereas the lipoprotein remnants in the vesicle are transferred to lysosomes and degraded by lysosomal acid

hydrolases, releasing free cholesterol, amino acids, FA, and phospholipids. These compounds can be reutilized by the cell. [Note:

Lysosomal storage diseases result from rare autosomal-recessive deficiencies in the ability to hydrolyze lysosomal cholesteryl esters  (Wolman disease) or to transport free cholesterol out of the lysosome  (Niemann-Pick disease, type C).]

2. Endocytosed cholesterol and cholesterol homeostasis: The chylomicron remnant–, IDL-, and LDL-derived cholesterol affects cellular cholesterol content in several ways (see Fig. 2). First, expression of the gene for HMG CoA reductase is inhibited by high cholesterol, and de novo cholesterol synthesis decreases as a result. Additionally, degradation of the reductase is accelerated. Second, synthesis of new LDL receptor protein is reduced by decreasing the expression of the LDL receptor gene, thus limiting further entry of LDL-C into cells. [Note: As was seen with the reductase gene), transcriptional regulation of the LDL receptor gene involves an SRE and SREBP-2. This allows coordinate regulation of the expression of these proteins.] Third, if the cholesterol is not required immediately for some structural or synthetic

purpose, it is esterified by acyl CoA:cholesterol acyltransferase (ACAT).

ACAT transfers a FA from a fatty acyl CoA to cholesterol, producing a

cholesteryl ester that can be stored in the cell (Fig. 3).

The activity of ACAT is enhanced in the presence of increased intracellular cholesterol.

Figure 3:  Synthesis of intracellular cholesteryl ester by ACAT. [Note:  Lecithin: cholesterol acyl transferase (LCAT) is the extracellular enzyme that esterifies cholesterol using phosphatidylcholine (lecithin) as the source of the fatty acid.] CoA = coenzyme A.

3. Uptake by macrophage scavenger receptors: In addition to the highly specific and regulated receptor-mediated pathway for LDL uptake described above, macrophages possess high levels of scavenger receptor activity. These receptors, known as scavenger receptor class A (SR-A),  can bind a broad range of ligands and mediate the endocytosis of chemically modified LDL in which the lipid or apo B component has been oxidized. Unlike the LDL receptor, the scavenger receptor is not

Down-regulated in response to increased intracellular cholesterol.

Cholesteryl esters accumulate in macrophages and cause their transformation into “foam” cells, which participate in the formation of atherosclerotic plaque (Fig. 4). LDL-C is the primary cause of atherosclerosis.

Figure 4:  Role of oxidized low-density lipoprotein (LDL) particles in plaque formation in an arterial wall.