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Lipoproteins Introduction

  • Definition and Importance

    • Lipids constitute a heterogeneous family of predominantly hydrophobic, and sometimes amphipathic, molecules.

    • In aqueous environments like the bloodstream, lipids are transported as complex macromolecular assemblies known as lipoproteins.

Structure of Lipoproteins

Composition of Lipoproteins

  • Heterogeneous Macromolecular Complexes

    • Comprised of lipids and specific proteins called apolipoproteins

  • Micelle-like Spherical Particles

    • Hydrophobic Core:

    • Contains triglycerides (TG), cholesteryl esters, and fat-soluble vitamins.

    • Outer Shell:

    • Thin monolayer composed of phospholipids and free cholesterol associated with apolipoproteins.

    • Components are amphipathic, ensuring solubility in aqueous biological fluids.

Classification of Lipoproteins

According to Density

  • Four main classes based on density and origin:

    1. Chylomicrons:

    • Origin: Intestinal

    1. Very low-density lipoproteins (VLDL):

    • Origin: Hepatic

    1. Low-density lipoproteins (LDL):

    • Formed from VLDL catabolism via intermediary density lipoproteins (IDL).

    1. High-density lipoproteins (HDL):

    • Origin: Hepatic and intestinal

  • Density-Size Relationship:

    • Larger lipoprotein particles have lower density; smaller particles have higher density.

According to Electrophoretic Migration

  • Plasma lipoproteins exhibit heterogeneous apolipoprotein and lipid compositions affecting their net electrical charge.

  • Separated by agarose gel electrophoresis, yielding four bands typically observed:

    • Chylomicrons: Remain at the origin

    • β-lipoproteins (LDL)

    • pre-β-lipoproteins (VLDL)

    • α-lipoproteins (HDL)

Composition of Different Lipoproteins

  • Chylomicrons:

    • Transport exogenous triglycerides (postprandial period).

  • VLDL:

    • Transport endogenous triglycerides.

  • LDL:

    • Transport cholesterol, mainly in the form of cholesteryl esters, to peripheral tissues.

  • HDL:

    • Facilitate reverse cholesterol transport, carrying cholesterol from peripheral tissues to the liver, and exchange phospholipids and apolipoproteins.

Study of Apolipoproteins

Definition

  • Apolipoproteins:

    • Five major classes: A, B, C, D, E (with subclasses).

  • Classified into two functional groups:

    • A/C/E Group:

    • Small, exchangeable (<100 kDa)

    • B Group (B-48, B-100):

    • Very large, non-exchangeable (>500 kDa); structural proteins for chylomicrons/VLDL/LDL.

Roles of Apolipoproteins

  • Structural Role:

    • Stabilize lipoprotein particles, ensuring solubilization in aqueous fluids, facilitating lipid transport.

  • Metabolic Role:

    • Act as ligands for cellular receptors (e.g., ApoE receptor, ApoB/E, LDL receptor).

    • Activate or inhibit enzymes involved in lipoprotein metabolism (e.g., lipoprotein lipase, LCAT).

Specific Apolipoproteins

  • Apolipoprotein B-48:

    • Main structural apolipoprotein of chylomicrons.

  • Apolipoprotein B-100:

    • Primary apolipoprotein in VLDL and LDL; integral non-exchangeable component secreted by hepatocytes.

  • Apolipoproteins A-I and A-II:

    • Main apolipoproteins of HDL.

  • Apolipoproteins E and C:

    • Exchangeable; synthesized mainly in the liver (ApoE also in macrophages); circulate primarily on HDL, transferring between lipoprotein particles during metabolism.

Lipoprotein Metabolism

Enzymes Involved

  1. Lipoprotein Lipase (LPL):

    • Location & Function:

    • Found in adipose tissue and skeletal/cardiac muscle; hydrolyzes triglycerides in chylomicrons and VLDL.

    • Produces chylomicron remnants and VLDL remnants (IDL) lacking triglycerides.

    • Facilitates uptake of released fatty acids by tissues for oxidation or storage.

    • Activators/Inhibitors:

    • Requires ApoC-II as an activator; inhibited by ApoC-III.

  2. Hepatic Lipase (HL):

    • Location & Function:

    • Synthesized by the liver; bound to hepatic capillary endothelial cells; hydrolyzes triglycerides and phospholipids in IDL, converting them into LDL.

    • Involved in HDL remodeling by converting HDL₂ into HDL₃ and/or pre-β₁ HDL.

  3. Lecithin–Cholesterol Acyltransferase (LCAT):

    • Location & Function:

    • Associated with HDL; esterifies free cholesterol, promoting HDL maturation.

    • Activator:

    • ApoA-I is the primary activator (ApoA-IV may also contribute).

Overview of Lipoprotein Metabolism

Chylomicron Metabolism

  • Formation in enterocytes post-meal and rich in triglycerides containing apoB-48.

  • Acquire apoC-II and apoE from HDL.

  • LPL hydrolyzes triglycerides → releases free fatty acids.

  • Chylomicron remnants are taken up by the liver.

  • Role: Transport dietary (exogenous) triglycerides.

VLDL / IDL Metabolism

  • Formed in the liver, comprises endogenous triglycerides and cholesterol, containing apolipoprotein B-100.

  • Released into circulation and acquire apoC-II and apoE from HDL.

  • LPL action hydrolyzes triglycerides → releases free fatty acids to tissues, returning apoC-II to HDL.

  • Converted into IDL.

  • Liver Uptake:

    • IDL taken up via LDL receptors (B/E) and LRP (apoE-dependent).

  • Remaining IDL loses apoE, enriched in cholesteryl esters, converts into LDL.

  • Role: Transport endogenous triglycerides.

LDL Metabolism

  • Formed in plasma from VLDL via IDL after triglyceride removal and loss of apoC and apoE, resulting in particles rich in cholesteryl esters.

  • Fates:

    • Peripheral Tissues:

    • Uptake via receptor-mediated endocytosis (cholesterol delivery).

    • Liver:

    • Major clearance through LDL receptor-mediated endocytosis.

    • Macrophages:

    • Uptake of modified (oxidized) LDL via scavenger receptors → formation of foam cells.

  • Intracellular Fate:

    • Cholesterol used for membranes/steroid synthesis; excess esters via ACAT.

  • Role of LDL:

    • Transport of cholesterol to peripheral tissues.

Note on LDL and Atherosclerosis

  • Atherosclerosis is a chronic inflammatory disease affecting the intima of arteries, promoted by oxidized LDL.

  • Complications include endothelial dysfunction, stenosis, and thrombosis.

HDL Metabolism

  • Synthesized in the liver/intestine as lipid-poor apoA-I particles (discoidal HDL).

  • Collect free cholesterol and phospholipids from peripheral cell membranes.

  • ApoA-I activates LCAT, enhancing HDL maturation (discoidal → spherical).

  • HDL serves as a reservoir for apolipoproteins (mainly apoC-II and apoE), exchanged with chylomicrons and VLDL.

  • Through CETP-mediated exchange, HDL transfers cholesteryl esters to apoB-containing lipoproteins and receives triglycerides.

  • Cholesteryl esters are mostly delivered to the liver and steroidogenic tissues via SR-B1 (selective uptake).

  • Role of HDL:

    • Ensure reverse cholesterol transport, removing excess cholesterol from tissues to the liver while also serving as a circulating reservoir for phospholipids and apolipoproteins.