Study Notes on Lipoprotein Metabolism

Lipoprotein Metabolism

Associated Readings

  • Gropper Ch. 5 (pp. 151-159)

  • Harper's Biochemistry Ch. 25-26

Thought Questions

  1. What are the characteristic features and primary roles of the 4 major classes of lipoproteins?

  2. Where and how are these lipoproteins assembled?

  3. How do dietary perturbations of fasting and feeding affect the assembly and metabolism of the lipoproteins?

  4. What roles do specific apoproteins play in the functionality of the respective lipoproteins?

  5. How does the [cholesterol] within cells, especially the hepatocytes, regulate LDL cholesterol concentrations in the blood?

  6. What are heterozygous and homozygous familial hypercholesterolemias and what is the etiology of these phenotypes?

  7. How do statin drugs and nicotinic acid improve the blood lipid profile?

Generalized Structure of Plasma Lipoproteins

  • Spherical particles containing:

    • Neutral Lipids: Triglycerides (TAGs) and Cholesteryl Esters (CE) in the interior.

    • Surface Components: Phospholipids, Cholesterol, and Proteins (Apolipoproteins).

  • Visual representation:

    • Core: contains TAG and CE

    • Surface Layer: consists of amphipathic phospholipids, free cholesterol, and proteins

    • Specific Component Structure:

    • Phospholipid

    • Protein

    • Cholesteryl Ester

    • Cholesterol

    • Triacylglycerol

  • Critical note: Differences in proportions of components exist across various classes of lipoproteins.

Types of Lipoproteins

  • Chylomicron (CM):

    • Function: Transports exogenous (dietary) lipids from gut to tissues.

  • Chylomicron Remnant:

    • Function: Transport dietary lipids to liver (associated with coronary heart disease risk).

  • Very-Low-Density Lipoprotein (VLDL):

    • Function: Transport endogenous triglycerides from liver to tissues.

  • Intermediate-Density Lipoprotein (IDL):

    • Function: Produced in plasma from VLDLs as TAGs and cholesterol are removed.

  • Low-Density Lipoprotein (LDL):

    • Function: Produced in plasma from IDLs; transports cholesterol to tissues.

  • High-Density Lipoprotein (HDL):

    • Function: Responsible for reverse cholesterol transport.

Apolipoproteins

  • Definition: Protein portion of a lipoprotein that affects structure and function.

  • Abbreviations: Typically abbreviated as 'apo', named with letters from A-E and may include subclassification (e.g., Apo C-II, Apo B-48).

Table of Apolipoproteins in Human Plasma Lipoproteins

Apolipoprotein

Lipoprotein(s)

Molecular Mass (Da)

Additional Remarks

apoA-1

HDL, Chylomicrons

28,000

Activator of Lecithin: cholesterol acyltransferase (LCAT); ligand for HDL receptor.

apoA-2

HDL, Chylomicrons

17,000

Structure comprises two identical monomers joined by a disulfide bridge.

apoA-4

Secreted with chylomicrons

46,000

Associated with triacylglycerol-rich lipoproteins; function unclear.

apoB-100

LDL, VLDL, IDL

550,000

Synthesized in the liver; ligand for LDL receptor.

apoB-48

Chylomicrons, Chylomicron remnants

260,000

Synthesized in the intestine.

apoC-1

VLDL, HDL, Chylomicrons

7,600

Potential activator of LCAT.

apoC-2

VLDL, HDL, Chylomicrons

8,916

Activator of extrahepatic lipoprotein lipase.

apoC-3

VLDL, HDL, Chylomicrons

8,750

Contains several polymorphic forms depending on the content of sialic acids.

apoD

Subfraction of HDL

20,000

Possible antioxidant.

apoE

VLDL, HDL, Chylomicrons, Chylomicron remnants

34,000

Ligand for chylomicron remnant receptor.

Assembly and Secretion of Triacylglycerol-rich Lipoproteins

  • Chylomicrons are formed in the enterocytes using:

    1. Fatty Acids (FA): From dietary fats metabolized to form TAG.

    2. Apolipoproteins: Including Apo B-48 (stabilizes chylomicrons) and Apo E/C from HDL.

  • Process: Chylomicrons package TAG to deliver necessary lipids to tissues.

  • Lipolysis: TAGs must be hydrolyzed by lipoprotein lipase (LPL) to free fatty acids (FFA) for cellular uptake.

Insulin and LPL Regulation

  • Insulin enhances the transcription and activity of LPL primarily in adipose tissue, while inhibiting LPL in skeletal muscle.

  • Catecholamines have the opposite effects: they lower LPL mRNA levels in adipocytes and promote its activity in muscle.

Lipoprotein Lipase (LPL)

  • Definition: Enzyme on the endothelial cell surfaces that hydrolyzes TAGs into FAs and glycerol.

  • Activation: Stimulated by insulin and activated by Apo C-II as a cofactor.

Key Points of Lipid Transport Pathways

  1. Exogenous Pathway: Involves the transport of dietary TAGs via chylomicrons, which later become remnants after delivering lipids to non-hepatic tissues.

  2. Endogenous Pathway: Involves VLDL transporting liver-derived TAGs to peripheral tissues and ultimately transforming to IDL, then LDL.

  3. Reverse Cholesterol Transport: Involved in HDL metabolism where HDL captures excess cholesterol from peripheral tissues and transports it back to the liver for excretion or reutilization.

Regulation of Cholesterol Metabolism

  • **Homeostasis Mechanisms:

    • Regulation of HMG Co-A Reductase (rate-limiting enzyme in cholesterol synthesis).

    • Feedback inhibition by intracellular cholesterol levels.

    • Hormonal regulation through phosphorylation (insulin activates, glucagon inhibits).

    • Incorporation of dietary cholesterol and cholesterol biosynthesis regulation in the liver.

Conclusion

  • Understanding the roles and mechanisms of lipoproteins and their apolipoproteins is critical for comprehending lipid metabolism, its health implications, and therapeutic interventions for hyperlipidemia.