Lipoproteins and Heart Disease

Lipoproteins

• Lipoproteins are spherical, macromolecular complexes of lipids and specific 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 their composition of lipids and proteins, size, density, and origin.
• Lipoproteins keep their component lipids soluble as they transport them through the plasma.
• Lipoproteins provide a mechanism for transporting their lipid contents to and from tissues.

Specific Objectives

• Understand the composition of different types of plasma lipoproteins.
• Explain the effect of lipoproteins in heart diseases.

Function of Lipoproteins

• The transport system in humans is less perfect compared to other animals. This results in gradual deposition of lipids, especially cholesterol, in tissues.
• Lipid deposition leads to plaque formation, causing narrowing of blood vessels (atherosclerosis).

Composition of Plasma Lipoproteins

• Lipoproteins are composed of a neutral lipid core (containing triacylglycerol and cholesteryl esters), surrounded by a shell of amphipathic apolipoproteins, phospholipid, and non-esterified (free) cholesterol.
• Triacylglycerols and cholesterol can be obtained from diet (exogenous) or from de novo synthesis (endogenous).

Size and Density of Lipoprotein Particles

• Chylomicrons have the lowest density and are the largest in size, containing the highest percentage of lipid and the lowest percentage of protein.
• VLDLs and LDLs have successively higher densities and higher ratios of protein to lipid.
• HDL particles are the densest.

Apo-Lipoproteins

• The protein part of a lipoprotein is called apolipoprotein (apo-Lp) or apoprotein.
• Apoproteins are primarily synthesized in the liver, but small quantities are produced from other organs. Intestinal cells produce apo-A.
• Types of apolipoproteins include:
  • Apo-A-I: Activates lecithin-cholesterol acyl transferase (LCAT), is a ligand for HDL receptor, and is anti-atherogenic.
  • Apo-B-100: A component of LDL, binds to LDL receptor on tissues, is one of the largest proteins, and is synthesized in the liver.
  • Apo-B-48: Synthesized in intestinal cells, is a structural component of chylomicrons, and is 48% the size of B-100.
  • Apo-C-II: Activates lipoprotein lipase.
  • Apo-E: Arginine-rich protein present in chylomicrons, LDL, and VLDL. Astrocytes also produce apo-E, and it is 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. The Apo E-IV isoform is implicated in senile dementia and Alzheimer's disease, and Apo-E also is associated with lipoprotein glomerulopathy.

Synthesis of Chylomicrons

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

Function of Chylomicrons

• Chylomicrons transport dietary triglycerides from the intestines to adipose tissue for storage and to muscle or heart for energy needs.
• Main sites of chylomicron metabolism are adipose and skeletal muscle.
• The half-life of chylomicrons in blood is about 1 hour.
• Lipoprotein lipase (LpL) is located at the endothelial layer of capillaries in adipose tissue, muscles, and heart, but not in liver.
• Apo C-II activates Lpl; Lpl hydrolyses triglycerides into fatty acids and glycerol.
• Muscle or adipose tissue cells take up the liberated fatty acids.
• Lack of C-II leads to decreased Lpl activity, resulting in accumulation of chylomicrons and VLDL.

Metabolism of VLDL

• VLDLs are synthesized in the liver.

• They are composed predominantly of endogenous triacylglycerol (approximately 60%), along with hepatic cholesterol, apo-B-100, C-II, and E.

• Apo-B-100 is the major lipoprotein present in VLDL when secreted.

• Apo-E and C-II are obtained from HDL in plasma.

• VLDL's function is transporting lipids from the liver to peripheral tissues for energy needs.

• "Fatty liver" (hepatic steatosis) occurs in conditions where there is an imbalance between hepatic triacylglycerol synthesis and VLDL secretion (e.g. obesity, uncontrolled diabetes mellitus, and chronic ethanol ingestion).

• VLDL half-life in serum is about 1 to 3 hours.

• Upon reaching peripheral tissues, apo-C-II activates LpL, which liberates fatty acids taken up by adipose tissue and muscle.

• The remnant is now designated as IDL (intermediate-density lipoprotein or VLDL remnants) and contains less TAG and more cholesterol.

• The major fraction of IDL loses triglycerides to be converted into LDL (low density lipoprotein).

• This conversion is the lipoprotein cascade pathway.

Metabolism of LDL

• LDL particles contain much less triacylglycerol 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 liver to peripheral tissues.
• Cholesterol liberated in the cell can be used to synthesize other steroids (e.g., steroid hormones), incorporated into membranes, or esterified to a MUFA by acyl cholesterol acyl transferase (ACAT) for storage.

LDL and Clinical Applications

• LDL concentration in blood is positively correlated with cardiovascular disease incidence.
• LDL infiltrates arterial walls and is taken up by macrophages (scavenger cells).
• This is the starting event of atherosclerosis, leading to myocardial infarction.
• Engorged macrophages with cholesterol are called "foam cells" which are deposited in subendothelial space causing atheromatous plaque formation.
• Procoagulant changes are induced in endothelium, increasing thrombosis and coronary artery disease chances.
• LDL-cholesterol deposition in tissues is called "bad cholesterol".

Metabolism of HDL

• HDL particles are formed in blood by adding lipids to apo-A-1 (an apolipoprotein made by liver and intestine).
• The major apoproteins in HDL are Apo-A1 (70%), along with some apo-A2, apo-C, and apo-E.
• HDL acts as a plasma reservoir of apo-C and apo-E, which can be transferred to VLDL and chylomicrons and back.

Functions of HDL

• HDL is the main transport form of cholesterol from peripheral tissues to the liver, where it's excreted via bile. This is called reverse cholesterol transport.
• The only excretory route for cholesterol is via bile.
• Cholesterol excretion requires prior esterification with PUFA. PUFA helps lower cholesterol levels and acts as an anti-atherogenic agent.

Clinical Significance of HDL

• HDL serum levels are inversely related to myocardial infarction incidence.
• HDL is considered "anti-atherogenic" or "protective" and is known as "good cholesterol".
• "H" in HDL stands for "healthy".
• HDL levels below 35 mg/dl increase risk, while above 60 mg/dl protects against coronary artery diseases.

Role of Lipoprotein (a)

• Lipoprotein (a) (Lp(a)) is a particle that, when present in large quantities in plasma, is associated with an increased risk of coronary heart disease.

• Lp(a) is strongly associated with myocardial infarction and sometimes called the "little rascal".

• Blood Lp(a) concentration exceeding 30 mg/dl makes individuals susceptible to heart attacks at a younger age.

• Lp(a) is structurally similar to an LDL particle.

• Factors like diet (e.g., trans fatty acids) can increase Lp(a) levels, while estrogen decreases both LDL and Lp(a) levels.

This quiz explores the structure and function of lipoproteins, focusing on their roles in human health. Understand the various types of lipoproteins, their lipid composition, and their significant impact on heart diseases. Test your knowledge on how lipoproteins transport lipids and contribute to vascular health.