Structural Biochemistry/Lipids/Lipoproteins

What is the role of Lipoproteins in the organism?
Cholesterol and triacylglycerols are transported in body fluids in the form of lipoprotein particles. There are three main reasons for transport.

1)	Lipoprotein particles are the means by which triacylglycerols are delivered to tissues, from the intestine or liver, for use as fuel or for storage. 2)	The fatty acid consists of triacylglycerol components of the lipoprotein particles are incorporated into phospholipids for membrane synthesis. 3)	Cells cannot degrade the steroids, thus cholesterol must be used in some biochemical reaction or get excreted by the liver.

Lipoproteins function in maintaining cholesterol homeostasis, transporting the molecule from site to site (synthesis to biochemical action), and lastly to the liver for excretion.

Lipoprotein Structure
Each lipoprotein particle consists of a core of hydrophobic lipids surrounded by a shell of relatively more polar lipids and proteins. The protein components of these aggregates, known as apoproteins, have two main roles:

1)	They solubilize hydrophobic lipids 2)	Contain cell targeting signals

Due to the diversity of steroids, there are different classes of lipoprotein particles and are classified according to increasing density. From lowest to greatest density: chylomicrons, chylomicron remnants, very low density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Although these classes of lipoproteins have many subtypes, these are the main classes that scientists have compiled based on density, diameter, and composition of various lipid components (i.e. presence of triacylglycerol, cholesteryl ester, free cholesterol, phospholipid, protein).

The following present the physiological roles of each class of lipoproteins:

-	Chylomicrons: triacylglycerols, cholesterol, and other lipids obtained from the diet are carried away to the intestine in the form of chylomicrons.

-	Very low density lipoprotein (VLDL): excess triacylglycerols and cholesterol in the liver are exported into the blood in the form of VLDLs.

-	Intermediate-density lipoproteins: These particles do two different tasks. Half of them are absorbed by the liver for processing, and the other half are converted in to low-density lipoprotein (LDL) by the removal of more triacylglycerol by tissue lipases that absorb the released fatty acids.

-	Low-density lipoprotein (LDL): is the major carrier of cholesterol in blood. The role of LDL is to transport cholesterol to peripheral tissues and regulate cholesterol synthesis at these sites.

-	High density lipoprotein (HDL): often referred to as “good cholesterol.” HDL functions as a shuttle that releases cholesterol in all areas of the body.

Importance of LDL
Cells outside the liver and intestine obtain cholesterol from the plasma rather than synthesizing itself. More specifically, their primary source of cholesterol is the low-density lipoprotein. Cells follow receptor-mediated endocytosis for LDL uptake. Receptor-mediated Endocytosis begins with LDL particle binds to a specific receptor protein on the membrane. The receptor on the cell surface is known as a clathrin. It is localized in special regions called coated pits that contain these clathrins. The receptor-LDL complex is then internalized by endocytosis. After internalization, the endosome is acidified, causing the receptor to release the LDL. The LDL vesicles subsequently fuse with lysosomes, which are acidic vesicles that carry a wide array of degradative enzymes. The LDL component is hydrolyzed to free amino acids. The cholesteryl esters in LDL are hydrolyzed by a lysosomal acid lipase.

The released un-esterified cholesterol can be used for membrane biosynthesis. Alternatively, it can be re-esterified for storage inside the cell.

The absence of LDL receptor
In familial hypercholesterolemia, cholesterol is deposited in various tissues because of the high concentration of LDL cholesterol in the plasma. The disease results from a mutation at a single autosomal locus and leads to higher than normal levels of cholesterol. The cholesterol level in the plasma of homozygotes is roughly around 680 mg/dl, compared to 300 mg/dl in heterozygotes. Although “normal” cholesterol levels differ from family to family, a 200 mg/dl or low concentration is considered normal for most people. In fact it is known that most homozygotes for this mutation die early in their childhood from coronary artery disease. The molecular defect in most cases of familial hypercholesterolemia is an absence or deficiency of functional receptors for LDL.

Receptor mutations disrupt almost every stage of the endocytosis pathway. Homozygotes have no functional receptors for LDL, whereas heterozygotes have about half the normal number. This varying ability is what is known as incomplete dominance in genetics.

HDL protection
Although atherosclerosis takes place rapidly in some, in others it takes place in people who develop atherosclerosis over decades. Over this long period of time, foam cells and plaques form. HDL and its role in returning cholesterol to the liver are important in mitigating life-threatening circumstances. HDL has many good properties, including the inhibition of LDL oxidation and removal of cholesterol from cells, especially macrophages. HDL undergoes a reverse cholesterol transport where it retrieves cholesterol form other tissues in the body to return the excess/bad cholesterol to the liver for excretion. The more HDL, the more readily the transport of LDL and macrophages to liver occurs. Hence, it is less likely that the macrophages will develop into foam cells.