User:Johnsy/Lipoprotein Modelling/Lipoprotein Structure and Function

Structure

Lipids are transported in lipoproteins throughout the circulation due to the fact that lipids are insoluble in the aqueous medium of blood. All lipoproteins contain the basic five components.

Figure 1 Structure of a Lipoprotein. [[1]]

1. Phospholipid monolayer - serves as a barrier between the hydrophobic interior containing triglycerides and cholesterol esters and the hydrophilic exterior defined by the extracellular fluid or blood plasma.
2. Apoproteins - proteins which span the phospholipid monolayer and act as signalling molecules to identify the contents and type of lipoprotein. Each type of lipoprotein has a different apoprotein coat distinguishing them from each other. Apoproteins also serve to interact with the outside aqueous environment as receptor ligands. HDL lipoproteins are characterized by the A-I apoprotein while VLDL, IDL, and LDL are chacterized by having the B-100 apoprotein. Chylomicrons have the B-48 apoporotein.
3. Free cholesterol embedded on the phospholipid monolayer whose polar alcohol groups on the unesterified cholesterol project into the aqueous environment.
4. Triglycerides - one method by which fatty acids and lipids are transported, usually contained in the core of the lipoprotein. Different lipoprotein classes contain different proportions of triglycerides and cholesterol esters.
5. Cholesterol Esters - esterified cholesterol attached to fatty acids (e.g. cholesterol linoleate) utilizing the hydroxyl group on cholesterol to form the ester bond. Cholesterol is transported mainly as cholesterol esters.

Classes

There are five different classes of lipoproteins, separated by composition, diameter, density and sources.

Table 1 Liprotein Classes (from Feher and Richmond, Lipids and Lipid Disorders, 1997)

1. Chylomicrons - Primarily responsible for transporting triglycerides
2. VLDL (very low density lipoprotein) - Produced by the liver and also responsible for transporting triglycerides and cholesterol esters
3. IDL (intermediate density lipoprotein) - Produced from the catabolism of VLDLs, contains a higher proportion of cholesterol esters than VLDL.
4. LDL (low density lipoprotein) - Produced from the catabolism of VLDL, contains the highest proportion of cholesterol ester of all lipoproteins, up to two-thirds of the cholesterol in the human plasma is found in LDL particles. [1]
5. HDL (high density lipoprotein) - Produced in the liver and intensine from the catabolism of chylomicrons and VLDL. Has the lowest proportion of cholesterol ester and triglyceride than any other lipoprotein.

Key Enzymes Associated with Lipoproteins

Several enzymes are required to maintain homeostasis of blood cholesterol levels and ensure that cells receive enough cholesterol to survive. The following are key enzymes that are help to maintain the level of cholesterol in the plamsa.

• Lipoprotein Lipase (LPL) - an extracellular enzyme attached to the cell via heparin sulphate to the endothelial lining of the capillaries perfusing muscle and adipose tissue. LPL hydrolyzes the the triglyceride in the lipoproteins allowing the fatty acids to be transferred to adipose tissue for stroage or to the muscle and liver for metabolic requirements. When VLDL is subjected to the action of LPL, the triglycerides are removed, increasing the percentage of cholesterol esters in the lipoprotein as well as shrinking it. Furthermore, surface remnants (lamellar complexes, unesterified cholesterol, phospholipids, and Apo A and C) are removed leaving behing an IDL. The surface remnants are recycled and join the HDL pool and are an important source of HDL precursors. Chylomicrons undergo similar removal of triglycerides when acted on by LPL, also resulting in an IDL.
• Adipose tissue mobilizing lipase (ATML) - an intracellular enzyme that couters the effect of LPL by hydrolyzing adipose tissue to release free fatty acids into the circulation, especially in times of fasting.
• Hepatic Lipase (HL) - a similar enzyme to LPL secreted by hepatic parenchymal cells and functions to hydrolyze IDL glycerides to produce chylomicron remnants (from chylomicrons) or LDL (from VLDLs). HL is also used to further hydrolyze HDL and LDL glycerides to promote receptor mediated uptake of LDLs and reverse cholesterol transport in HDL.
• Lecithin cholesterol acyl transferase (LCAT) - an enzyme synthesized in the liver and responsible for esterfying free cholesterol acquired by HDL particles by transfer of a fatty acid from lecithin. The esterified cholesterol is then transferred to the core of the particle forming a cholesterol ester-rich HDL2.
• Cholesterol ester transfer protein (CETP) - an enzyme that catalyses the transfer of cholesterol esters from HDL and LDL particles to triglyceride rich lipoproteins

Lipoprotein Receptors

• LDL Receptor - The LDL receptors binds lipoproteins with Apo B-100 and/or Apo E apoproteins (LDL or IDL). The main role of this receptors is to provide cholesterol to the cells throughout the body and deliver excess cholesterol to the liver for recycling or excretion as bile acids. As stated before, the LDL receptor is a major control point in the control of cholesterol levels. The synthesis of receptors is in response to a fall in cellular free cholesterol concentration. The LDL particles bind to the receptor, are internalized, and are subject to lysosomal degradation. Following the LDL particle degradation, the receptors themselves are recycled and either stored if the cellular concentration of cholesterol is high enough or returned to the cell surface if cellular cholesterol levels remain lower than desired.
• Chylomicron remnant (Apo E) receptor - This receptor is mainly in the liver where chylomicron remnants are quickly removed from circulatioin. This receptor is not down-regulated by cholesterol levels, but delivery of cholesterol via this route will down-regulate the synthesis of LDL receptors.
• HDL receptors - HDL receptors are up-regulated by cholesterol loading and allow HDL particles to bind to extra-hepatic (non liver) tissues resulting in a net efflux of cholesterol from the cell.

References

1. Brown MS and Goldstein JL. Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3330-7. DOI:10.1073/pnas.76.7.3330 |