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Lipoprotein Biochemistry - Complete Notes
1. Introduction to Lipoproteins
- Lipoproteins are water-soluble macromolecules that carry lipids (water-insoluble) in blood plasma and deliver them to various tissues.
- TAG and cholesterol are transported in blood as lipoproteins.
- Named according to density - density increases with the percentage of protein in the particle.
Major lipids in plasma:
- Triglycerides (TG)
- Phospholipids
- Cholesterol
- Cholesterol ester
- FFA (metabolically most active form)
Major lipoproteins identified (by electrophoresis):
- Chylomicron (Origin)
- VLDL (Pre-β)
- LDL (β)
- HDL (α)
2. Structure of Lipoprotein
- Spherical particles with a hydrophobic core (TAG + esterified cholesterol) with apolipoprotein on the surface.
- Core: mainly nonpolar lipids
- Surface: monolayer of mainly amphipathic lipids + peripheral apolipoproteins (e.g., Apo C) + integral apolipoproteins (e.g., Apo B)
3. Plasma Lipid Profile
Sample of serum taken after 12-14 hours of fasting
| Types | Normal | Low Risk | Borderline | High Risk |
|---|---|---|---|---|
| Total cholesterol | 140-200 mg/dl | <200 | 200-240 | >240 |
| LDL cholesterol | 80-130 mg/dl | <130 | 130-160 | >160 |
| HDL cholesterol | 35-60 mg/dl | >60 | 35-60 | <35 |
| Triacylglyceride | 50-150 mg/dl | <150 | 200-400 | >400 |
4. Characterization of Lipoproteins in Human Plasma
| Property | Chylomicron | VLDL | LDL | HDL |
|---|---|---|---|---|
| Electrophoretic mobility | Origin | Prebeta | Beta | Alpha |
| Density | <0.96 | 0.96-1.006 | 1.006-1.063 | 1.063-1.21 |
| Diameter (nm) | 100-1000 | 30-90 | 20-25 | 10-20 |
| Apolipoprotein | B48, A-I, A-II | B100, C-I, C-II | B100 | A-I, A-II, C-II |
| Protein (%) | 2 | 10 | 20 | 40 |
| Lipid (%) | 98 | 90 | 80 | 60 |
| Triglycerides (% of lipid) | 88 | 55 | 12 | 12 |
| Cholesterol esters | 4 | 24 | 59 | 40 |
| Phospholipids | 8 | 20 | 28 | 47 |
| Free fatty acid | - | 1 | 1 | 1 |
5. Metabolism of Chylomicrons
Synthesis: Formed in intestinal mucosal cells, secreted into lacteals of lymphatic system. Rich in TG. Contain Apo B-48 + apo-A; apo-C and apo-E derived from HDL during transport.
Metabolic pathway:
- Intestine → Nascent chylomicron (Apo B-48, Apo-A, dietary TAG)
- Acquires Apo-C, Apo-E + cholesterol esters from HDL → mature chylomicron
- Apo-C activates lipoprotein lipase (LPL) in capillaries of adipose tissue, muscle, heart
- LPL hydrolyses chylomicron into:
- Chylomicron remnant (with B-48, Apo-E) → taken up by liver via Apo-E dependent receptors (LDL receptor protein) → cholesterol esters + triacylglycerol hydrolyzed and metabolized
- Apo-A, Apo-C → taken back by HDL
- Fatty acids + glycerol → transported to adipose tissue, muscle
Functions of chylomicrons:
- Transport dietary TAG from intestine to adipose tissue for storage
- Supply to muscle and heart for energy
Note: Heparin releases LPC from tissues - clears lipemia (post-heparin lipolytic cutting). Insulin increases LPL activity.
6. VLDL & LDL
VLDL Synthesis:
- Synthesized in liver from glycerol and fatty acids
- Most LDL particles derived from VLDL; a small part released from liver
- Apo-B100 is major apolipoprotein of VLDL
- The only apo protein in LDL is Apo-B100
VLDL Metabolic pathway:
- Liver → Nascent VLDL (liver TAG, Apo B-100)
- Acquires Apo-C, Apo-E + cholesterol esters from HDL → mature VLDL
- Apo-C activates LPL
- LPL hydrolyses VLDL into:
- VLDL remnant/IDL (cholesterol, few TAG, B-100, Apo-E) → gains cholesterol esters + provides TAG to HDL → turns into LDL → taken up by liver via LDL receptor (Apo B-100, Apo E receptor)
- Apo-C → taken by HDL
- Fatty acids + Glycerol → transported to adipose, muscle
VLDL Functions:
- 75% of plasma cholesterol incorporated into LDL
- Transport endogenous TG from liver to peripheral tissue for energy
- Transport cholesterol from liver to peripheral tissue
Note: Half-life of LDL = 2 days in plasma. LP(a) strongly associated with MI ("little rascal").
LDL Clinical Significance:
- Increases risk of atherosclerosis → myocardial infarction
- Called "bad cholesterol"
- Increased/modified LDL (glycation in DM, oxidation) → taken up by macrophages as foam macrophages
- Oxidized LDL found in cigarette smokers, DM, insulin resistance patients
7. HDL (High Density Lipoprotein)
Metabolism:
- Intestine + liver synthesize nascent HDL (Apo A-1 + free cholesterol) - discoid shaped
- Apo A-1 activates LCAT (Lecithin Cholesterol Acyl Transferase) in plasma
- LCAT converts cholesterol → cholesterol esters → spherical HDL-3
- ABC-A1 + ABC-G1 transfer cholesterol from peripheral tissue to HDL
- LCAT continues converting cholesterol to cholesterol esters → HDL-3 → HDL-2
- HDL-2 taken up by liver via SRB-1 receptor → cholesterol excreted in bile
- HDL-2 may be reconverted to HDL-3 by hepatic lipase
Functions of HDL:
- Transport cholesterol from peripheral tissues to liver (reverse cholesterol transport)
- The only excretory route of cholesterol from body is bile
Clinical significance:
- HDL cholesterol is anti-atherogenic and good cholesterol
8. Free Fatty Acids (FFA)
- Also called non-esterified fatty acid
- Complexed with albumin in plasma
- Derived from lipolysis of PG stored in adipose tissue by hormone sensitive lipase (HSL)
- May be long chain saturated or unsaturated
- In tissue cell, FFA-albumin complex disassociated → FFA binds fatty acid transport protein → enters cell → bound to fatty acid binding protein
- Half-life of FFA in plasma: only 1-2 minutes
- During starvation, 40-50% of energy met by FFA oxidation
- Blood FFA: very low (fed state), very high (uncontrolled DM + starvation)
9. Apo-Lipoproteins
| Apo | Function |
|---|---|
| APO A-I | Ligand for HDL receptor, anti-atherogenic, activates LCAT |
| APO A-II | Dimer mainly in HDL, activates hepatic lipase |
| APOB-48 | Only in chylomicron; 48% size of B-100 |
| APOB-100 | Principal protein in LDL, one of the biggest proteins |
| APO C-I | In CM, VLDL, HDL - activates LCAT |
| APO C-II | In CM, VLDL, HDL - activates lipoprotein lipase |
| APO C-III | In CM, VLDL, HDL - inhibits lipoprotein lipase |
| APO E | In CM, VLDL, IDL, LDL (arginine rich) |
Note: APO-A (major constituent of HDL; "A" is in capital - anti-atherogenic and present in all persons). LP(a) seen in high levels in some persons - "a" is in small letter - highly atherogenic.
10. Key Enzymes in Lipoprotein Metabolism
| Enzyme | Function |
|---|---|
| Lipoprotein lipase | Hydrolyses TG into FFA and Glycerol |
| ACyl-CoA: Cholesterol Acyl Transferase (ACAT) | Esterifies cholesterol intracellularly |
| LCAT/PCAT | Esterifies cholesterol extracellularly (in HDL) |
| Cholesterol Ester Transfer Protein (CETP) | Exchanges CHE and TG between HDL and LDL |
| ATP Binding Cassette Protein A1 (ABCA1) | Mediates efflux of cholesterol to HDL |
| Scavenger Receptor (SR-B1) | Class B scavenger receptor, dual role in HDL metabolism |
11. Fredrickson's Classification of Lipoprotein Disorders
| Type | Name | Feature | Treatment |
|---|---|---|---|
| Type I | Familial Hyperchylomicronemia | Massive fasting hyperchylomicronemia; deficiency of LPL or Apo CII; NOT associated with CHD | Low-fat diet; no drug therapy |
| Type IIA | Familial Hypercholesterolemia | Elevated LDL, normal VLDL; block in LDL degradation; increased serum cholesterol, normal TG; accelerated ischemic heart disease | Cholestyramine + niacin or statin |
| Type IIB | Familial Combined (Mixed) Hyperlipidemia | Like IIA but VLDL also increased → elevated TG + cholesterol; caused by VLDL overproduction; relatively common | Diet + drug therapy similar to IIA |
| Type III | Familial Dysbetalipoproteinemia | Increased IDL → elevated TG + cholesterol; mutant ApoE; xanthomas + accelerated vascular disease | Diet, niacin + fenofibrate or statin |
| Type IV | Familial Hypertriglyceridemia | Elevated VLDL, normal/low LDL; overproduction/decreased removal of VLDL; obese, diabetic, hyperuricemic patients | Diet, niacin and/or fenofibrate |
| Type V | Familial Mixed Hyertriglyceridemia | Elevated VLDL + chylomicrons; LDL normal/decreased; genetic defect | Diet, fenofibrate |
12. Other Notable Conditions
Tangier Disease:
- Excessive catabolism of HDL & Apo A-1 → low HDL → hypolipoproteinemia
- Mutation in ABC-1 (ATP-binding cassette protein) in 13q region
Fish Eye Disease: Partial LCAT deficiency
Abetalipoproteinemia:
- Mutation in microsomal TG transfer protein
- Deficiencies in ApoB48 and ApoB100
- Metabolism of chylomicron and VLDL severely affected
Dysbetalipoproteinemia = Type III hyperlipidemia
13. Atherosclerosis and Plasma Lipoprotein
- HDL plays a major role in reverse cholesterol transport (scavenging action) - prevents atherosclerosis
- LDL deposits cholesterol in smooth muscle cells of arteries → atherosclerosis
- Increased LDL → increased MI risk
- Endogenous lipoproteins: VLDL, LDL, HDL
- Exogenous lipoprotein: Chylomicron
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