Apolipoprotein Deep Dive

Apolipoproteins: An Overview

Apolipoproteins are proteins associated with lipoproteins, which are particles assembled from triglycerides, cholesterol esters, phospholipids, free cholesterol, and apolipoproteins themselves. Lipoproteins transport water-insoluble substances throughout the body. Apolipoproteins have multiple functions.

Abbreviations to remember:

  • Apo, apoprotein, and apolipoprotein are all interchangeable terms.
  • ApoB-48 is a 48% truncated version of ApoB-100.
  • ApoA-1 is the same as ApoA-I (Roman numeral).
  • ApoC-2 is the same as ApoC-II (Roman numeral).

Apolipoprotein Types: Exchangeable vs. Non-Exchangeable

Apolipoproteins reside on the surface of lipoprotein particles and can be categorized as either non-exchangeable or exchangeable.

Non-Exchangeable Apolipoproteins

These remain with their lipoprotein particle throughout its lifespan:

  • ApoB-48:
    • Found on all intestinal-origin lipoproteins (chylomicrons).
    • Present from assembly to chylomicron remnant uptake by hepatocytes.
    • Aids hepatocytes in identifying the particle for recycling.
  • ApoB-100:
    • Present on liver-origin lipoproteins (VLDL, IDL, and LDL).
    • Present throughout the particle's existence.

Exchangeable Apolipoproteins

These can transfer between different lipoprotein particles:

  • ApoA-1:
    • Associated with HDL.
    • Enables the conversion of cholesterol to cholesterol esters via activation of LCAT (lecithin-cholesterol acyltransferase).
    • Acquired from the liver (80%) or small intestine (20%).
  • ApoC-2:
    • Activates lipoprotein lipase (LPL) in capillaries.
    • Essential for chylomicrons and VLDL to release triglycerides (TAGs) to adipocytes.
    • Acquired from HDL.
  • ApoE:
    • Interacts with LDL receptors, facilitating endocytosis of VLDL and chylomicron remnants into hepatocytes.
    • Given to VLDL and chylomicrons by HDL.

Significance of Apolipoprotein Exchange

  • ApoC-2 Deficiency: Without enough HDL to donate ApoC-2, VLDL and chylomicrons remain immature, carrying lipids (including cholesterol) and lingering in circulation, raising the risk of atherosclerosis.
  • ApoE Deficiency: Similarly, without ApoE, VLDL and chylomicrons remain longer in circulation than they should, increasing the risk of atherosclerosis.

Apolipoprotein Functions: Tissue Targeting

  • ApoB-48: Targets chylomicron remnants to remnant receptors in the liver.
  • ApoB-100:
    • Found on VLDL, IDL, and LDL.
    • Enables LDL to bind to LDL receptors on cell surfaces for cholesterol delivery.
    • The only apolipoprotein on LDL particles.
  • ApoE: Facilitates endocytosis of VLDL and chylomicron remnants by the liver.

Apolipoprotein Functions: Enzyme Activation

  • ApoA-1: Activates LCAT, which esterifies free cholesterol into cholesterol esters, enabling reverse cholesterol transport.
    • Free Cholesterol+Fatty Acid→LCATCholesterol Ester\text{Free Cholesterol} + \text{Fatty Acid} \xrightarrow{\text{LCAT}} \text{Cholesterol Ester}
    • Cholesterol esters are a safe, non-atherogenic form of cholesterol for transport.
    • Free cholesterol is atherogenic.
  • ApoC-2: Activates lipoprotein lipase in capillaries.

Apolipoprotein Composition of Lipoproteins

  • Chylomicrons:
    • Start with ApoB-48.
    • Acquire ApoC-2 and ApoE from HDL.
    • Return ApoC-2 to HDL after use.
    • ApoB-48 and ApoE are taken up during liver recycling.
  • VLDL:
    • Made in the liver with ApoB-100.
    • Acquire ApoC-2 and ApoE from HDL.
    • Become IDL as they release TAGs.
  • IDL:
    • Taken up by the liver via ApoE and ApoB-100.
    • Can also lose more TAG and become LDL.
    • Give up APO C-2 to HDL.
  • LDL:
    • Only contain ApoB-100.
  • HDL:
    • Receive ApoA-1 from liver (80%) and intestines (20%).
    • Give ApoC-2 and ApoE to VLDL and chylomicrons.
    • Take ApoC-2 from VLDL and chylomicron remnants.

ApoC-2 & Lipoprotein Lipase (LPL)

ApoC-2 activates LPL which is expressed on endothelial cells, to hydrolyze TAG within lipoprotein particles into free fatty acids, allowing absorption into tissues.

Chylomicron and HDL Interaction

  1. Dietary lipids are absorbed in the small intestine and assembled into nascent chylomicrons (containing only ApoB-48).
  2. HDL donates ApoE and ApoC-2 to nascent chylomicrons, turning them into mature chylomicrons.
  3. ApoC-2 enables mature chylomicrons to interact with LPL in capillaries, releasing free fatty acids and glycerol.
  4. After releasing fatty acids, the chylomicron becomes a chylomicron remnant, returning ApoC-2 to HDL.
  5. The chylomicron remnant (containing ApoE and ApoB-48) is recognized by E receptors on the liver and taken up for recycling.

VLDL Processing

The process is similar to chylomicrons:

  1. Nascent VLDL particles become mature by acquiring ApoC-2 and ApoE from HDL.
  2. Mature VLDL particles give off their TAGs.
  3. APOC-2 returns to HDL.

Approximately >90% of ApoC-2 returns to HDL from chylomicron and VLDL particles.

Fate of Chylomicron Remnants

Once depleted of TAG, chylomicron remnants are enriched in cholesterol esters and return to circulation. They give up ApoC-2 to HDL, allowing the liver to recognize ApoE and take them up.

Lipid Metabolism During Fasting

During fasting, VLDLs supply TAG-derived fatty acids to tissues. VLDLs are synthesized in the liver from TAG, cholesterol, and ApoB-100, and are immobilized on capillary endothelial cells by LPL, which is activated by ApoC-2 (obtained from HDL).

Fate of VLDL Particles

  • After releasing TAGs, VLDL becomes a VLDL remnant, giving its ApoC-2 back to HDL.
  • VLDL remnants can be taken up by the liver via the E receptor, or they can lose ApoE to become LDL.

LDL Characteristics

  • Rich in cholesterol esters.
  • Supply cholesterol to tissues.
  • Small particles (10 nm diameter).
  • Each LDL particle has one molecule of ApoB-100.

ApoB-100 as an Atherosclerosis Indicator

ApoB-100 levels in circulation are a more accurate reflection of atherogenic lipoprotein burden than LDL cholesterol levels, as it also reflects VLDL and IDL particle concentrations.

LDL Receptor Deficiency: Familial Hypercholesterolemia

  • Prevalence: ~0.2%.
  • Autosomal dominant inheritance.
  • Heterozygotes: 2-3x increase in LDL cholesterol.
  • Homozygotes: 6-8x increase in LDL cholesterol.
  • Results in early atherosclerosis and coronary artery disease.
  • Statins may be less effective in homozygotes due to defective LDL receptors.

Glycosylation of ApoB-100

Glycosylated ApoB-100 promotes uptake of LDLs by macrophages and smooth muscle cells via scavenger receptors, leading to foam cell formation. This is exacerbated in diabetes mellitus due to hyperglycemia.

Lipoprotein (a) [Lp(a)]

  • A modified form of LDL with apolipoprotein (a) attached.
  • Apolipoprotein (a) directs Lp(a) particles to sites of trauma.
  • Elevated Lp(a) levels increase atherosclerosis risk.
  • More common in people of recent African ancestry.

HDL Particles

HDLs contain LCAT and carry apolipoproteins for other lipoprotein particles, and also participate in reverse cholesterol transport.

APOA-1 & Cholesterol Loading of HDL

HDL docks at cholesterol-replete cells via APOA-1, including foam cells, and APOA-1 activates LCAT to convert cholesterol into cholesterol esters, which are then transported into the HDL core, forming a mature HDL particle.

Lipid Metabolism in Adipocytes

  • Insulin promotes TAG storage by converting extracellular free fatty acids into intracellular TAG.
  • Insulin inhibits hormone-sensitive lipase (HSL), which breaks down TAG into free fatty acids.

Diabetes and Lipoprotein Metabolism

  • Insulin Deficiency/Resistance: Leads to increased HSL activity, releasing free fatty acids into circulation. The free fatty acids get repackaged into TAG in the liver, which are then packaged into VLDL particles which contributes to elevated VLDL and cholesterol levels.
  • Hyperglycemia:
    • Increases apolipoprotein C3 expression, inhibiting lipoprotein lipase activity and prolonging the circulation of cholesterol.
    • Increases LDL glycosylation, leading to increased macrophage uptake via scavenger receptors and foam cell formation.

Summary

  • Chylomicrons and VLDL supply TAG.
  • LDL supplies cholesterol.
  • HDL facilitates reverse cholesterol transport.
  • Apolipoproteins determine lipoprotein metabolism and fate.
  • Diabetes increases atherosclerotic plaque formation.