Lipids are a structurally diverse group of compounds.
Lipids are hydrophobic molecules, hence insoluble in water.
How are they transported in light of this?
Lipids are transported in blood bound to carriers
How are different types of lipids transported in the blood?
- ~ 2% of lipids (fatty acids) are carried bound to albumin (limited capacity)
- ~ 98% of lipids are carried as lipoprotein particles consisting of phospholipid, cholesterol, cholesterol esters, proteins & TAG
Describe the structure of a phospholipid molecule
Where are phospholipid molecules seen?
Describe the formation and function of cholesterol
- Formation: some obtained from diet, but most synthesised in liver
- Function: essential component of membranes (modulates fluidity)
Cholesterol also acts as a precursor for several molecules.
- Precursor of steroid hormones e.g. cortisol, aldosterone, testosterone
- Precursor of bile acids
How is cholesterol transported?
Transported around body as cholesterol ester
Describe the structure of a lipoprotein molecule
What are the contents of a lipoprotein molecule?
What are the two types of apolipoproteins found on a lipoprotein molecule?
There are five distinct classes of lipoproteins named according to density.
- VLDL (very low density lipoproteins)
- IDL (intermediate density lipoproteins)
- LDL (low density lipoproteins)
- HDL (high density lipoproteins)
Illustrate how each type of lipoprotein contains variable content of apolipoprotein, triglyceride, cholesterol and cholesterol ester
Lipoprotein density is obtained by flotation ultracentrifugation.
What is the observed relationship between density and diameter?
Particle diameter is inversely proportional to density
Rank the different lipoprotein molecules according to their density and diameter
What is the relationship between lipoproteins and apolipoproteins?
Each class of lipoprotein particle has a particular complement of associated proteins (apolipoproteins)
Which two apolipoproteins are of clinical significance?
- apoB (VLDL, IDL, LDL)
- apoAI (HDL)
Identify the two roles of apolipoproteins
- Structural: packaging water insoluble lipid
- Functional: co-factor for enzymes and ligands for cell surface receptors
In 8 steps, outline chylomicron metabolism
⇒ In small intestine, apoB-48 added to chylomicrons before entering lymph
⇒ Travel to thoracic duct & empties into left subclavian vein
⇒ Acquire 2 new apoproteins (apoC and apoE) once in blood
⇒ apoC binds lipoprotein lipase on adipocytes and muscle
⇒ Released FA enter cells depleting fat content in chylomicron
⇒ Chylomicron remnants return to liver
⇒ LDL receptor on hepatocytes binds apoE, chylomicron remnant taken up by receptor mediated endocytosis
⇒ Lysosomes release remaining contents for metabolic use
What are chylomicron remnants?
Chylomicron remnants are molecules formed when triglyceride content is reduced to ~20% and apoC dissociates
What is lipoprotein lipase and where is it found?
- LPL is an enzyme that hydrolyses TAG in lipoproteins and requires ApoC-II as cofactor
- It is found attached to surface of endothelial cells in capillaries
In 5 steps, outline VLDL metabolism
⇒ In liver, apoB100 added during formation
⇒ apoC and apoE added from HDL particles in blood
⇒ VLDL binds to LPL on endothelial cells in muscle and adipose
⇒ TAG content depletes
⇒ Released FA used for energy production (muscle) / re-synthesis of TAG and fat storage (adipose)
In four steps, explain how IDL and LDL are formed from VLDL
⇒ VLDL particles dissociate from LPL as TAG content depletes and return to liver
⇒ IDL particle is formed if VLDL content depletes to ~30% (short lived)
⇒ IDL particles can return to liver / rebind to LPL enzyme to further deplete TAG content
⇒ LDL particle is formed if depletion to ~ 10% as IDL loses apoC & apoE
Illustrate the relationship between VLDL, IDL and LDL metabolism
Describe the structure and function of the LDL particle
- Structure: do not have apoC or apoE, hence aren't efficiently cleared by liver (liver LDL-Receptor has a high affinity for apoE)
- Function: provide cholesterol from liver to peripheral tissues (peripheral cells LDL receptor takes up LDL via receptor mediated endocytosis)
The IDL particle is short lived in comparison to the LDL particle.
What is the clinical relevance of this?
- Half life of LDL in blood is much longer than VLDL or IDL making LDL more susceptible to oxidative damage
- Oxidised LDL taken up by macrophages that can transform to foam cells and contribute to formation of atherosclerotic plaques
In four steps, describe how LDL enters peripheral cells by receptor mediated endocytosis
⇒ Cells requiring cholesterol express LDL receptors on plasma membrane
⇒ apoB-100 on LDL acts as a ligand for these receptors
⇒ Receptor/LDL complex taken into cell by endocytosis into endosomes
⇒ Fuse with lysosomes for digestion to release cholesterol and fatty acids
What controls the receptor-mediated endocytosis of LDL in peripheral cells?
LDL receptor expression controlled by cholesterol concentration in cell
Describe the three possible pathways for the synthesis of HDL
- Synthesised by liver and intestine (low TAG levels)
- Bud off from chylomicrons and VLDL as they are digested by LPL
- Free apoA-I acquires cholesterol and phospholipid from other lipoproteins and cell membranes
How do HDL particles mature?
- Nascent HDL accumulates phospholipids and cholesterol from cells lining blood vessels
- Hollow core progressively fills and particle takes on more globular shape