Review of Lipoproteins March 21, 2003 Bryant Miles Lipids by definition are insoluble in water. In order to transport lipids such as fatty acids, triacylglycerols, steroids and fat soluble vitamins in the blood plasma, a carrier protein is required. Fatty acids are carried from the adipose tissue to the muscle, heart and liver tissues by serum albumin. Vitamin A is carried by the retinol binding protein. There are steroid carrier proteins that carry steroids to the target cells. The bulk of the body’s lipids (cholesterol, phospholipids and triacylglycerols), are transported in the plasma by large complexes called lipoproteins. These lipoproteins consist of a core of hydrophobic lipids surrounded by a shell of phosphotidyl glycerols and proteins. The protein components of lipoproteins solubilize the hydrophobic lipids and contain the cell targeting signals. Lipoproteins are classified according to their density. The lowest density lipoproteins are the chylomicrons followed by the chylomicron remnants, very low density lipoproteins VLDLs, intermediate density lipoproteins, IDLs, low density lipoproteins, LDLs, and high density lipoproteins, HDLs. The densities of these lipoproteins are related to the relative amounts of lipids to proteins in the complex. The higher the protein content the higher the density of the lipoprotein. Low Density Lipoprotein Shown to the left is a low density lipoprotein. The core of the LDL is composed of triacylglycerols and cholesteryl esters. This lipid core is surrounded by a layer of amphipathic phospholipids and unesterified cholesterol. The lone hydroxyl group of cholesterol molecules is oriented towards the outer surface shown here as black dots. The lipoproteins also contain apoproteins in their outer shell. The apoproteins have important roles in lipid transport and metabolism. They have specific structural domains that are recognized by cell receptors. All of the apoproteins have amphipathic α-helixes with the hydrophobic side chains facing the lipid interior of the lipoprotein and the hydrophilic residues interacting with the polar head groups of the phospholipids or interacting with the aqueous solvent. The affinities of the apoproteins for the surface components of the lipoprotein change during lipoprotein metabolism. Apoproteins often diffuse from one lipoprotein and bind to another. Only apoprotein B maintains its association with the lipoprotein during the cycle of lipoprotein metabolism. Chylomicrons Dietary lipids are carried from the intestinal mucosa cells to other tissues by lipoproteins called chylomicrons. Chlyomicrons are large and have the lowest protein to lipid ratio and hence have the lowest density of all the lipoproteins. Chylomicrons contain phospholipids and proteins on the surface so that the hydrophilic surfaces are in contact with water. The hydrophobic molecules are enclosed in the interior. The principle apoproteins of nascent chylomicrons are apo B-48, apo A-I, apo A-II and apo A-IV. In circulation, the nascent chylomicrons acquire apo-C and apo-E from plasma HDL in exchange for phospholipids. The acquisition of apo-CII from HDL is essential to activate lipoprotein lipase, LPL. Chylomicrons bind to membrane bound lipoprotein lipases (LPLs) located on adipose and muscle tissues where the triacylglycerols are hydrolyzed into fatty acids. The fatty acids are transported into the adiposecell where they are once again resynthesized into triacylglycerols and stored. In the muscle, the fatty acids are oxidized to provide energy. As the tissues absorb the fatty acids, the chylomicrons progressively shrink until they are reduced down to cholesterol enriched remnants. As the chylomicron shrinks it transfers a substantial portion of its phospholipids and apoproteins A and C to HDL. The apo C proteins are continuously recycled between chylomicrons and HDL. The remnants lacking apo A and C proteins do not bind to the LPLs in the capillaries. The remnants are rapidly absorbed by the liver. Lipoprotein Lipases Chylomicrons bind to Lipoprotein Lipases located in the capillaries of the tissues. Apo-CII is required to activate the LPLs. The LPLs hydrolyze the fatty acid ester bonds liberating glycerol and free fatty acids. The fatty acids are absorbed by the endothelial cells that line the capillary. LPL is serine esterase that is found primarily in muscle and adipose tissue. LPL is secreted out of the cell and is translocated to the lumenal surface of the endothelial cells lining the capillary where it is attached to heparin sulfate. LPL is the major enzyme involved in the processing of chylomicrons and VLDLs. Human Apoproteins Apoprotein Lipoprotein Classes Function A-I Chylomicrons, HDL Activates LCAT A-II Chylomicrons, HDL Inhibits LCAT, enhances hepatic lipase activity. A-IV Chylomicron Unknown function B-100 VLDL, IDL, LDL Necessary for binding to cell receptors, LPLs. B-48 Chylomicron Necessary for binding to cell receptors, LPLs. C-I Chylomicron, VLDL, HDL Cofactor for LCAT C-II Chylomicron, VLDL, HDL Activates LPL C-III Chylomicron, VLDL, HDL Regulates LPL D HDL Essential for LCAT activity and Cholesteryl ester transfer. E All Binds to specific cell receptors.Very Low Density Lipoproteins The liver synthesizes fatty acids and cholesterol and packages them for transport in the blood plasma in VLDLs. Normally the cholesterol is unesteried and found as a surface component of the lipoprotein. A high cholesterol diet alters the composition of the VLDL with cholesteryl esters substituting for triacylglycerols as the primary constituent of the lipid core. The primary apoprotein is B-100. The liver secretes VLDLs via exocytosis. Like chylomicrons, VLDLs undergoe constant changes in the plasma. First, the nacent VLDL acquires apo C and E from HDL. VLDLs bind to the same membrane bound lipoprotein lipases (LPLs) located on adipose and muscle tissues where the triacylglycerols are hydrolyzed into fatty acids. The fatty acids are transported into the adipose cell where they are once again resynthesized into triacylglycerols and stored. In the muscle, the fatty acids are oxidized to provide energy. As the tissues absorb the fatty acids and monoacylglycerols, the VLDLs progressively shrink forming IDLs. As the VLDL shrinks it transfers a substantial portion of its phospholipids and apoprotein C to HDL. IDLs can bind to receptors of liver cells where they are