Enzyme Explorer

Lipoprotein Function


Lipoprotein Function and Lipid Transport

Products for Lipoprotein Research

Overview
Classification of Lipoproteins and the Systemic Pathway of Lipids
Apolipoprotein Classification, Properties and Function

Plasma & Blood Protein Resource


Overview

Cholesterol is an essential nutrient required structurally for cell membranes and myelin sheaths. Functionally cells require cholesterol as a precursor to bile acids and steroid hormones. The liver produces approximately 70% of the ~1 gram of cholesterol utilized daily by a normal adult. The other 30% comes from dietary intake.

Contrary to popular understanding, when we speak of "good and bad" blood cholesterol levels, we are not speaking of different types of cholesterol molecules. Due to their poor solubility in the blood stream, cholesterol, triglycerides and other lipids require transport vehicles such as lipoprotein particles. It is these transport vehicles that determine the "good and bad" nature of cholesterol.

There are five main classifications of lipoproteins. However, the "good and bad" terminology normally refers to High Density Lipoproteins (HDL) and Low Density Lipoproteins (LDL) respectively. Lipoproteins differ in their content of proteins and lipids. The higher the ratio of protein to lipid content the higher the density. In general, the higher the density of a lipoprotein particle the smaller it's size and molecular weight.

Low HDL (<35 mg/dL), may be associated with increased risk of coronary atherosclerosis, conversely high levels of HDL (>55 mg/dL) appear to have a protective affect. High LDL levels have been shown to correlate with coronary atherosclerosis. A normal fasting individual has LDL concentrations ranging from 200 - 300 mg/dL.

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Classification of Lipoproteins and the Systemic Pathway of Lipids

In general lipoprotein particles range in size from 10 to 1000 nm. They are composed of a hydrophobic core containing cholesteryl esters, triglycerides, fatty acids and fat-soluble vitamins. The surrounding hydrophilic layer is composed of various apolipoproteins, phospholipids and cholesterol.

 

 


Chylomicrons

Chylomicrons are the largest (1000 nm) and least dense (<0.95) of the lipoproteins. They contain only 1-2% protein, 85-88% triglycerides, ~8% phospholipids, ~3% cholesteryl esters and ~1% cholesterol. Chylomicrons contain several types of apolipoproteins including apo-AI,II & IV, apo-B48, apo-CI, II & III, apo-E and apo-H.

Chylomicrons are produced for the purpose of transporting dietary triglycerides and cholesterol absorbed by intestinal epithelia. Chylomicron assembly originates in the intestinal mucosa. Excretion into the plasma is facilitated through the lymphatic system. In the plasma, chylomicrons acquire apo-CII and apo-E from HDL. Once transported to tissues, triglycerides contained in chylomicrons are hydrolyzed by apo-CII-dependent activation of lipoprotein lipase contained on the endothelial cell walls. The chylomicron remnant, including residual cholesterol, is taken up by the liver via receptor-mediated endocytosis by recognition of it's apo-E component.

Very Low Density Lipoproteins (VLDL)

Very low density lipoproteins are the next step down from chylomicrons in terms of size and lipid content. They are approximately 25-90 nm in size (MW 6-27 million), with a density of ~0.98. They contain 5-12% protein, 50-55% triglycerides, 18-20% phospholipids, 12-15% cholesteryl esters and 8-10% cholesterol. VLDL also contains several types of apolipoproteins including apo-B100, apo-CI, II & III and apo-E. VLDL also obtains apo-CII and apo-E from plasma HDL.

VLDL assembly in the liver involves the early association of lipids with apo-B100 mediated by microsomal triglyceride transfer protein while apo-B100 is translocated to the lumen of the ER. Lipoprotein lipase also removes triglycerides from VLDL in the same way as from chylomicrons.

Intermediate Density Lipoproteins (IDL)

Intermediate density lipoproteins are smaller than VLDL (40 nm) and more dense (~1.0). They contain the same apolipoproteins as VLDL. They are composed of 10-12% protein, 24-30% triglycerides, 25-27% phospholipids, 32-35% cholesteryl esters and 8-10% cholesterol.

IDLs are derived from triglyceride depletion of VLDL. IDLs can be taken up by the liver for reprocessing, or upon further triglyceride depletion, become LDL.

Low Density Lipoproteins (LDL) and Lipoprotein(a)

Low density lipoproteins are smaller than IDL (26 nm) (MW approximately 3.5 million) and more dense (~1.04). They contain the apolipoprotein apo-B100. LDL contains 20-22% protein, 10-15% triglycerides, 20-28% phospholipids, 37-48% cholesteryl esters and 8-10% cholesterol.

LDL and HDL transport both dietary and endogenous cholesterol in the plasma. LDL is the main transporter of cholesterol and cholesteryl esters and makes up more than half of the total lipoprotein in plasma. LDL is absorbed by the liver and other tissues via receptor mediated endocytosis. The cytoplasmic domain of the LDL receptor facilitates the formation of coated pits; receptor-rich regions of the membrane. The ligand binding domain of the receptor recognizes apo-B100 on LDL, resulting in the formation of a clathrin-coated vesicle. ATP-dependent proton pumps lower the pH inside the vesicle resulting dissociation of LDL from its receptor. After loss of the clathrin coat the vesicles fuse with lysozomes, resulting in peptide and cholesteryl ester enzymatic hydrolysis. The LDL receptor can be recycled to the cell membrane. Insulin, tri-iodothyronine and dexamethasome have shown to be involved with the regulation of LDL receptor mediated uptake.


Lipoprotein(a) is similar in structure to LDL. However, it contains a additional protein, apolipoprotein(a) (apo-(a)), covalently bound to apo-B. Apo-(a) has been found to have a high sequence homology with plasminogen. It contains variable amounts of repeating kringle regions and more than 40 isoforms with a MW range of 400-700 kD. Its function is thought to be related to triglyceride metabolism and possibly thrombotic and atherogenic pathways.

High Density Lipoproteins

High density lipoproteins are the smallest of the lipoproteins (6-12.5 nm) (MW 175-500KD) and most dense (~1.12). HDL contains several types of apolipoproteins including apo-AI,II & IV, apo-CI, II & III, apo-D and apo-E. HDL contains approximately 55% protein, 3-15% triglycerides, 26-46% phospholipids, 15-30% cholesteryl esters and 2-10% cholesterol.

HDL is produced as a protein rich particle in the liver and intestine, and serves as a circulating source of Apo-CI & II and Apo-E proteins. The HDL protein particle accumulates cholesteryl esters by the esterification of cholesterol by lecithin-cholesterol acyl-transferase (LCAT). LCAT is activated by apo-AI on HDL. HDL can acquire cholesterol from cell membranes and can transfer cholesteryl esters to VLDL and LDL via transferase activity in apo-D. HDL can return to the liver where cholesterol is removed by reverse cholesterol transport, thus serving as a scavenger to free cholesterol. The liver can then excrete excess cholesterol in the form of bile acids.

In a normal fasting individual, HDL concentrations range from 1.0-2.0 g/L.

References

  1. Mills, G.L., et al., A Guidebook to Lipoprotein Technique, Elsevier:Amsterdam, New York and Oxford, 1984: p. 3.
  2. Olivecrona, T., et al., "Mechanism for the Removal of Chyle Triglyceride from the Circulating Blood as Studied with (14C)Glycerol and (3H)Palmitic Acid Labeled Chyle." Biochim Biophys. Acta, 98, 81 (1965).
  3. Brown, M. S., and Goldstein, J. L. "A receptor-mediated pathway for cholesterol homeostasis." Science, 232, 34-47 (1986).
  4. Fellin, R.B. et al., "Isolation and analysis of human plasma lipoproteins accumulating postrandial in an intermediate density fraction (d 1.006--1.019 g-ml)". Clin. Chim. Acta, 54, 325 (1974).
  5. Salter, A.M., et al. "Interactions of triiodothyronine, insulin and dexamethasone on the binding of human LDL to rat hepatocytes in monolayer culture". Atherosclerosis, 71,77-80 (1988).
  6. Spady, D.K. "Reverse cholesterol transport and atherosclerosis regression". Circulation. 100, 576-578 (1999).
  7. Marcovina, S.M. and Morrisett, J.D., "Structure and metabolism of lipoprotein(a)". Curr. Opin. Lipidol., 6,136-45 (1995).
  8. McLean, J.W.et al., "CDNA sequence of human apolipoprotein(a) is homologous to plasminogen". Nature, 300, 132-7 (1987).
  9. Liu, A.C. and Lawn, R.M., "Vascular interactions of lipoprotein(a)". Curr. Opin. Lipidol., 5, 269-73 (1994).

 

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