Lipoproteins: Structure and Function

• Lipids like cholesterol and TAGs are insoluble in plasma and circulate in lipoproteins.
• Lipoproteins transport lipids to tissues for energy, deposition, steroid hormone production, and bile acid formation.

Lipoproteins Composition

• Consist of esterified/unesterified cholesterol, TAGs, phospholipids, and proteins (apolipoproteins/apoproteins).
• Lipoproteins have a polar surface coat, a nonpolar lipid core, apoproteins, phospholipids, unesterified cholesterol, cholesterol ester and triglycerides.

Types of Lipoproteins

• Chylomicrons (CM) are the largest lipoproteins, carrying 98% dietary lipid and 2% protein, entering the lymph, and are also known as ultra low-density lipoproteins (ULDL).
• Very low-density lipoproteins (VLDL) carry endogenous TAG and cholesterol, with 95% lipid and 5% protein.
• Intermediate-density lipoproteins (IDL) carry cholesterol esters and triglycerides.
• Low-density lipoproteins (LDL) carry cholesterol to cells, composed of 80% lipid and 20% protein.
• High-density lipoproteins (HDL) contain 60% lipid and 40% protein, transporting excess cholesterol from cells to the liver.

Apolipoproteins

• They act as ligands for receptors and cofactors for enzymes, dictating the destination of lipoproteins.
• Cells recognize lipoproteins by their apoprotein content.
• There are many types of apolipoproteins.

Major Apolipoproteins

• A-I is the key structural protein for HDL and activates lecithin-cholesterol acyltransferase (LCAT).
• A-II serves as HDL’s structural protein and activates hepatic lipase.
• B-100 is the structural protein for VLDL, IDL, LDL, and Lp(a), which is a ligand for the LDL receptor.
• B-48 contains 48% of B-100, present in chylomicrons, and does not bind to the LDL receptor.
• C-I activates LCAT.
• C-II is an essential cofactor for lipoprotein lipase (LPL).
• C-III inhibits triglyceride hydrolysis by lipoprotein lipase (LPL) and hepatic lipase, interfering with endothelial function.
• Apo E acts as a ligand for the hepatic chylomicron and VLDL remnant receptor, facilitating the clearance of lipoproteins and acting as a ligand for the LDL receptor.
• Apo(a) is a structural protein for Lp(a) and inhibits plasminogen activation on Lp(a).

TAG Transport

• TAGs are transported from the intestines in chylomicrons (exogenous TAG) and from the liver in VLDL (endogenous TAG).
• Chylomicrons are found in chyle and formed by the lymphatic system draining the intestine, transporting dietary lipids into circulation.
• VLDL is of hepatic origin, transporting TAG from the liver to extrahepatic tissues.

Chylomicron Metabolism

• Chylomicrons formed in the small intestine (nascent CM) contain Apo B-48.
• Apo C-II (lipoprotein lipase activator) and apo E (CM remnant binding to liver receptor) are transferred from HDL to CM during its metabolism.
• Lipoprotein lipase (capillary endothelium) rapidly clears CM from the blood.
• Phospholipids and apo C-II act as its cofactors.
• It hydrolyzes TAGs to FFA + glycerol.
• FFA is transported into tissues, mainly to adipose tissue, heart, and muscle.
• Lipoprotein lipase (LPL) hydrolyzes 70-90% of the TAG of CM, with apo C-II returning to HDL and apo E remaining.
• The resulting chylomicron remnant is half the diameter of the parent CM, enriched in cholesterol and cholesteryl esters.
• Lipoprotein lipase activity is regulated by insulin, which stimulates lipoprotein lipase synthesis.
• The highest activity of lipoprotein lipase is in cardiac muscle, supplying energy needed for cardiac function.
• CE-rich CM remnants bind to specific receptors on the liver and are endocytosed.

VLDL Metabolism

• VLDLs are produced in the liver and composed of endogenous TAG (~60%).
• They carry endogenous TAG from the liver to peripheral tissues.
• In peripheral tissues, TAG is degraded by lipoprotein lipase, similar to CM.
• VLDL is secreted directly into the blood by the liver as nascent VLDL containing apo B-100.
• VLDL must acquire apo C-II and apo E from circulating HDL; apo C-II is needed for lipoprotein lipase activation.

LDL Metabolism

• LDL binds to specific receptors on extrahepatic tissues and the liver, where they are endocytosed.
• Primary function of LDL is to provide cholesterol to peripheral tissues.
• LDL binds to membrane LDL receptors that recognize apо В-100 (but not apo B-48).
• LDL receptors can bind apo E and are known as apo В 100/apo E receptors.
• LDL receptors are negatively charged glycoproteins clustered in pits on cell membranes and are coated with clathrin.
• LDL binds to its receptor, forming a complex internalized by endocytosis.
• Vesicles containing LDL lose their clathrin coat and fuse to form endosomes.
• Endosome pH falls, allowing the separation of LDL from the receptor.
• Receptors migrate to one side of the endosome and are recycled.
• LDL in the vesicle is transferred to lysosomes, degraded by lysosomal acid hydrolases, releasing free cholesterol, amino acids, fatty acids, and phospholipids.
• The released materials can then be reused by the cell.
• Prolonged circulation of LDL increases oxidative modification and atherogenicity.
• Defects in LDL-R synthesis lead to familial hypercholesterolemia.

HDL Metabolism

• HDL acts as an excellent acceptor for cholesterol, solubilizing it with its high phospholipid content.
• HDL contains apo A-I and A-II, apo C-II, and apo E.
• It serves as a circulating reservoir of apo C-II and apo E for CM and VLDL.
• It removes free cholesterol from peripheral tissues and esterifies it by lecithin:cholesterol acyltransferase (LCAT), which is activated by apo A-1.
• It delivers newly formed cholesteryl esters (CE) to the liver (reverse cholesterol transport).

Reverse Cholesterol Transport

• Reverse cholesterol transport relieves cholesterol burden of cells, making HDL anti-atherogenic.
• High plasma concentration of HDL-cholesterol (HDL-C) is associated with longevity, while decreased concentration of HDL-C (and apoAI) is associated with an increased CVD risk.
• Cholesterol delivered from peripheral cells to the liver by HDL is used in bile acid synthesis, disposed of via bile, and used by steroidogenic cells for steroid hormone synthesis.
• As discoidal nascent (liver, small intestine) HDL accumulates CE, it becomes spherical, first relatively CE-poor HDL3 and later on CE-rich HDL2 that carries CE to liver.
• The efflux of cholesterol from peripheral cells is partly mediated by the transport protein, ABCA1; an ATP-binding cassette (ABC) protein.
• The ATP-binding cassette (ABC) protein family uses energy from ATP hydrolysis to transport materials, including lipids, in and out of cells.
• Cholesterol ester transfer protein (CETP) moves some CE from HDL to VLDL in exchange for TAG.
• VLDL is catabolized to LDL, and CE is taken up by the liver.
• Uptake of CE by the liver is mediated by SR-B1 (scavenger receptor class B type 1), which binds HDL.
• Clearance of TG-rich lipoproteins (VLDL) from circulation is controlled by lipoprotein lipase (LPL), CETP, and hepatic lipase (HL).
• Hepatic lipase (HL) is regulated by HDL, which facilitates the clearance of TG from VLDL.
• Inverse relationship_exists between blood TG and HDL levels.
• HDL particles have distinct immunologic and antiatherogenic properties.
• Macrophage reverse cholesterol transport (MRCT) is one aspect of HDL functionality.
• HDL particles enter the subendothelial space, and participate in macrophage reverse cholesterol transport (MRCT) →antiatherogenic process.
• HDL attaches to foam cells (lipid-laden macrophages) and accepts cholesterol from them.
• Foam cells are a type of cell that contain cholesterol and can form a plaque, triggering myocardial infarction and stroke.
• Discoidal pre-betaHDL (unlipidated) is converted to spherical alpha-HDL (lipidated-HDL2) and accumulates cholesterol ester (CE) returning it to the liver by scavenger receptor SR-B1.

Lipoprotein (a)

• Lp(a) is nearly identical in structure to an LDL particle with an additional apolipoprotein, apo(a).
• Apo(a) shares structural homology to plasminogen, a precursor of plasmin that degrades fibrin.
• Lp(a) competes with plasminogen for binding to fibrin, slowing breakdown of blood clots.
• Elevated plasma levels are associated with thrombosis and increased risk of coronary heart disease.
• Niacin lowers Lp(a) levels by reducing apo(a) transcription and raising HDL.