LDL CHOLESTEROL LDL
cholesterol is low density lipoproteins. LDL is called the bad cholesterol, LDL is what will clog up your arteries. High LDL level in the blood is one of the leading causes of heart disease. These are some of the major sources of LDL : egg yolkes, fatty red meat, shrimps, lobster. Exercising and cutting back on fats does reduce LDL levels. Eat more fruits and vegetables and other foods rich in soluble fiber that includes oat bran and beans. An LDL level of 160 or higher is considered high, desirable LDL level is 130 or less. People with heart disease want to be below 100.
LDL particles retain apo B-100, but lose their other apolipoprotein to HDL. They contain much less triacylglycerol than their VLDL predecessors, and have a high concentration of cholesterol and cholesteryl esters.
1. Receptor - mediated en endocytosis : The primary function of LDL particles is rovide cholesterol to the peripheral tissues. They do so both by depositing free cholesterol on the membranes of cells as they come in contact with the cell surface, and by binding to receptors on cell-surface membranes that recognize apolipoprotein B-100.Cellular uptake and degradation of LDL:
LDL receptor are negatively charged glycoprotein molecules that are clustered in pits on cell membranes. The intracellular side of the pit is coated with the protein clathrin, which stabilizes the shape of the pit. {Note : A deficiemcy of functional LDL receptors causes a significant elevation in plasma LDL, and therefore of plasma cholesterol, but plasma triacylglycerol levels remain normal, for example, as in type II hyperlipidemia (familial hyperbetalipoproteinmia). This can greatly accelerate the progress of artherosclerosis.]
After binding, the LDL are internalized as intact particles by endocytosis.
The vesicle containing the LDL rapidly loses its clathrin coat and fuses with other similar vesicles, forming larger vesicles called endosomes.
the pH of the contents of the endosome falls (due to the proton-pumping activity of endosomal ATPase), allowing separation of the LDL from its receptor. The receptors then migrate to one side of the endosome, whereas, the LDL state free, within the lumen of the vesicle. [Note: This structure called CURL-the Compartment for Uncoupling of Receptor and Ligand.]
The receptors can be recycled, whereas the the lipoprotein remnants in the vesicle are degraded by lysosornal (hydrolytic enzymes, releasing cholesterol, amino acids, fatty acids, and phospholipids. These compounds can be recycled by its cell. [Note : The number of receptors for lipoproteins varies according to the availability of these lipoprotein particles and according to the needs of the cell for example, if there is a large amount of a particular circulating plasma lipoprotein, the number of cell-surface receptors for a decreases, frequently termed "down-regulation." Conversely of cell-surface receptors ("up-regulation").]
2. Effect of endocytosed cholesterol on cell cholesterol content. The chylomicron remnant -, HDL-, and LDL-derived cholesterol affects cellular cholesterol content is several ways First, HMG CoA reductase activity is inhibited by cholesterol so that de novo cholesterol synthesis decreases. Second if the cholesterol is not required immediately for some structural or synthetic purposes, it is esterified by acyl CoA: cholesterol acyltransferase (ACAT). ACAT transfers a fatty acid from a fatty acyl CoA derivative to cholesterol, producing a cholesteryl ester that can be stored in the cell .The activity of this enzyme is enhanced in the presence of increased intracellular cholesterol. Third synthesis of new LDL receptor protein is lowered by decreasing transcription of the LDL, gene so that further entry of LDL cholesterol into the cell is limited.
3. Uptake of chemically modified LDL by macrophage scavenger receptors: In addition to the highly specific receptor-mediated pathway for LDL described above, circulating macrophages possess high levels of scavenger receptors activity. These receptors, which have board ligand-binding specificity, can mediate the endocytosis of chemically modified LDL. Chemical modifications that convert circulating LDL into ligands that can be recognized by the receptors include acetylation or oxidation of apolipoprotein B. [Note: the initiating step in the modification of apoB involves the peroxidation of polyunsaturated fatty acids in the LDL lipids. This process can be inhibited by antioxidants such as vitamin E. Unlike that taken up by the LDL receptor, the modified LDL taken up by macrophages does not regulate intracellular cholesterol levels, therefore cholesterol accumulates in these cells. Excessive uptake of modified LDLs by macrophages causes the transformation of these cells into " foam" cells, which, participate in the formation of atherosclerotic plaques.
