Lipoproteins Overview

Lipoproteins are spherical macromolecular complexes composed of lipids and proteins (apolipoproteins).
Types of lipoprotein particles include chylomicrons (CM), very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
Lipoproteins differ in lipid and protein composition, size, density, and origin.
Lipoproteins keep their component lipids soluble during transport in the plasma.
They provide an efficient mechanism for transporting lipids to and from tissues.
In humans, lipid deposition occurs gradually, particularly cholesterol, in tissues.
Lipid deposition contributes to plaque formation, causing blood vessel narrowing (atherosclerosis).

Lipoproteins have a neutral lipid core (triacylglycerol and cholesteryl esters) surrounded by a shell of amphipathic apolipoproteins, phospholipid, and non-esterified cholesterol.
Triacylglycerol and cholesterol in lipoproteins originate either from the diet or from de novo synthesis.

Chylomicrons are the lowest density and largest lipoprotein particles, containing the highest percentage of lipid and lowest percentage of protein.
VLDL and LDL are successively denser and have a higher ratio of protein to lipid.
HDL particles are the densest.

The protein part of lipoproteins is called apolipoprotein or apoprotein.
Apoproteins are mainly synthesized in the liver, but small quantities are produced by other organs.
Intestinal cells produce some apo-A.
Apo-A-I activates lecithin-cholesterol acyl transferase (LCAT), acts as a ligand for HDL receptor, and is anti-atherogenic.
Apo-B-100 is a component of LDL, binds to LDL receptors in tissues, and is a major protein synthesized in the liver.
Apo-B-48 is synthesized in intestinal cells, a structural component of chylomicrons, and is 48% the size of Apo-B-100.
Apo-C-II activates lipoprotein lipase.
Apo-E is an arginine-rich protein found in chylomicrons, LDL, and VLDL.
Astrocytes also produce Apo-E, involved in cellular lipid transport in the central nervous system (CNS).
Apo-E exists as isoforms (I, II, III, and IV), due to independent alleles in the genes.
Apo-E isoforms are associated with senile dementia and Alzheimer's disease.
Apo-E is associated with lipoprotein glomerulopathy.

Chylomicrons are formed in intestinal mucosal cells.
They are rich in triglycerides.
Chylomicrons contain apo-B-48 and apo-A, but apo-C and apo-E are added from HDL during transport.

Chylomicrons transport dietary triglycerides from the intestines to adipose tissue for storage and to muscle/heart for energy needs.
Main sites of chylomicron metabolism are adipose tissue and skeletal muscle.
Half-life of chylomicrons in blood is about 1 hour.
Lipoprotein lipase (LpL) is located on endothelial cells of capillaries in adipose tissue, muscle, and heart (but not liver).

VLDLs are synthesized in the liver.
VLDLs primarily contain endogenous triglycerides (approximately 60%), along with hepatic cholesterol, apo-B-100, C-II and E.
Apo-B-100 is the major lipoprotein present in VLDLs.
Apo-E and C-II are obtained from HDL in the plasma.
VLDL's function is to carry lipids from the liver to peripheral tissues for energy needs.
"Fatty liver" (hepatic steatosis) occurs in conditions where there's an imbalance between hepatic triglyceride synthesis and VLDL secretion.
Conditions include obesity, uncontrolled diabetes mellitus, and chronic ethanol ingestion.
Half-life of VLDL in serum is 1-3 hours.
When reaching peripheral tissues, apo-C-II activates lipoprotein lipase (LpL), releasing fatty acids utilized by adipose tissue and muscle.
The remnant is now IDL (intermediate density lipoprotein), or VLDL remnant, containing less triglycerides and more cholesterol.
Most IDL converts to LDL (low-density lipoprotein).
This conversion is known as the lipoprotein cascade pathway.

LDL particles contain less triglycerides than their VLDL predecessors and have a high concentration of cholesterol and cholesteryl esters.
About 75% of plasma cholesterol is incorporated into LDL particles.
LDL transports cholesterol from the liver to peripheral tissues.
Cholesterol in cells has three major fates: synthesizing other steroids like hormones, incorporation into membranes, and esterification for storage.
Cellular cholesterol content regulates endogenous cholesterol synthesis by regulating HMG CoA reductase.

LDL concentration correlates positively with cardiovascular disease incidence.
LDL infiltrates arterial walls and is taken up by macrophages (scavenger cells).
This initiates atherosclerosis leading to myocardial infarction.
Engorged macrophages with cholesterol form foam cells, deposited in subendothelial spaces, triggering atheromatous plaque formation.
Procoagulant changes in endothelium increase thrombosis and coronary artery disease risk.
LDL cholesterol is known as "bad cholesterol" and LDL as "Lethally Dangerous Lipoprotein".

HDL particles are formed in blood by adding lipids to apo-A-1, an apolipoprotein made by the liver and intestine.
Major apoproteins in HDL are Apo-A1 (70%), with some Apo-A2, Apo-C, and Apo-E.
HDL serves as a plasma reservoir for Apo-C and Apo-E, capable of transfer to VLDL and chylomicrons, and vice versa.

HDL is the main transport form of cholesterol from peripheral tissues to the liver for excretion.
This is called reverse cholesterol transport.
The only cholesterol excretion route is via bile.
Cholesterol excretion needs prior esterification with polyunsaturated fatty acids (PUFAs).
Thus, PUFAs help lower cholesterol and are anti-atherogenic.

HDL levels inversely correlate with myocardial infarction incidence.
HDL is anti-atherogenic or protective, referred to as "good cholesterol."
"H" in HDL stands for "healthy."
HDL levels below 35 mg/dL increase risk, while levels above 60 mg/dL protect against coronary artery disease.

Lipoprotein (a) (Lp(a)) is associated with increased coronary heart disease risk.
Lp(a) is strongly associated with myocardial infarction and sometimes called the "little rascal."
High Lp(a) (over 30 mg/dL) increases susceptibility to heart attack at a younger age.
Lp(a) structure is nearly identical to an LDL particle.
Trans fatty acids increase Lp(a), and estrogen decreases both LDL and Lp(a).