L4: Lipid Transport Flashcards
What are lipids?
Structurally diverse, insoluble molecules
What are the different types of lipids?
Triacylglycerol (di and mono too) Fatty acids Cholesterol (cholesterol esters) Phospholipids Vitamins A, D, E and K
What is the problem with transport?
Insoluble cant transport in blood
Solution–> carrier molecules
2% lipids (mainly FA) bound to albumin
98% –> lipoprotein particles
What is the structure of a phospholipid?
Polar head (hydrophilic) –> classified according to this
Phosphate
Glycerol backbone
Non Polar tails (hydrophobic)- Fatty acids X2
How can phospholipids arrange themselves?
Bilayer sheet
Liposome–> bilayer in a sphere shape
Micelle
Where does cholesterol come from? What is it for?
Synthesised in liver
Component of membranes
Precursor steroid hormones –> cortisol, aldosterone, testosterone, oestrogen
Precursor bile acids
How is cholesterol transported around the body?
Cholesterol esters
Esterification –> Lecithin Cholesterol Acyltransferase (LCAT) or Acyl-coenzyme A cholesterol acyltransferase
What is the function of lipoproteins?
Transport lipids around the body Consist of phospholipid, cholesterol, cholesterol esters, proteins, TAG Cargo: - TAG - Cholesterol esters - Fat soluble vitamins A, D, E and K
What is the structure of a lipoprotein?
Phospholipid monolayer –> spherical
Small amount of cholesterol and apolipoproteins
–> Intergral (apoA and apoB) and peripheral (apoC and apoE)
What are the different classes of lipoproteins?
Chylomicrons –> Chylomicron remnants (lipid removed)
Very Low Density Lipoproteins (VLDL)
Intermediate Density Lipoproteins (IDL)
Low Density Lipoproteins (LDL)
High Density Lipoproteins (HDL)
Variable amounts of apolipoproteins, triacylglycrides, cholesterol and cholesterol esters in each
How was the density off lipoproteins discovered?
Flotation Ultracentrifugation –> separated
Particle diameter inversely proportional to density
What are apoplipoproteins?
Associated proteins
Lipoprotein specific
How many classes of apoplipoproteins are there?
6 major –> A, B, C, D, E and H
What are the most important apoplipoproteins?
apoB (VLDL, IDL, LDL) and apoAI (HDL)
What is the function of apoplipoproteins?
Structural role–> packaging of water insoluble lipids
Functional role–> Co-factor for enzymes
–> ligands for cell surface receptors
How are chylomicrons metabolised?
- Cargo loaded in small intestine
- apoB-48 added
- Enters lymphatic system –> thoracic duct –> left subclavian vein
- apoC and apoE added
- apoC binds lipoprotein lipase–> capillary wall of adipocytes and muscle
- Release fatty acids into cell
- TAG reduced to 20% apo C dissocites
- Chylomicron remenant–> liver
- LDL receptors hepatocytes–> bind apoE –> receptor mediated endocytosis
- Lysosomes released–> remaining contents for use in metabolism
How are VLDL metabolised?
- Made in liver–> transporting TAG
- apoB100 added liver
- apoC and apoE added by HDL particles in blood
- Binds lipoprotein lipase on endothelial cells
- Depleted of TAG
- -> muscle –> energy production
- -> adipose –> resynthesis of TAG or stored
How are IDL and LDL formed?
VLDL–> ↓TAG–> dissocaites LPL returned to liver
HOWEVER
VLDL depleted 30% –> IDL short lived–> returned to liver or attach (rebind) to lipoprotien lipase become more depleted
Depleted to 10% -> looses apoC and apoE –> LDL (high cholesterol content)
What is the function of low density lipoproteins?
Cholesterol from liver–> peripheral tissue
Peripheral tissue LDL receptor–> receptor mediated endocytosis–> cholesterol released–> lysosomal digestion
Cholesterol esters released –> converted free cholesterol
LDL no apoC or apoE so not cleared by liver
What is the clinical relevance of LDL particles?
LDL has a longer half life
Not cleared by liver (no apoE, liver has apoE receptor)
Susceptible to oxidative damage
Oxidised LDL–> macrophages–> foam cells –> atherosclerotic plaques
How does receptor mediated endocytosis work?
Cholesterol needing cell--> LDL receptor apoB100 ligand for receptors Endocytosed into endosome Fuse with lysosome--> digestions Release FA and Cholesterol LDL-R expression--> controlled--> by cholesterol concentration
What is lipoprotien lipase?
Enzyme
Removes TAG from lipoproteins –> hydrolyses –> FA and glycerol
Insulin ↑synthesis of enzymes
What is the function of Lecithin:Cholesterol Acyl transferase (LCAT)?
Removal of core lipids–> make lipoprotein unstable
Stability restored–> surface lipid converted to core lipid
LCAT required
Cholesterol converted to cholesterol esters
Important for formation of lipoproteins and maintenance of structure
How is HDL metabolised?
- Synthesised by liver and intestine
- HDL particles can also bud off chylomicrons and VLDL when digested by lipoprotein lipase
- Free apoAI-> acquires cholesterol and phospholipid from other lipoprotiens and cell membranes–> HDL
What is the function of HDL?
Remove excess cholesterol –> liver or other cells
How does HDL remove cholesterol?
Nacent HDL (empty) Removes from cells lining blood vessels
Hollow core fills up
No enzyme activity
What is reverse cholesterol transport?
HDL –> Removal of cholesterol from cholesterol laden cells
Reduces likelihood of foam cells and artherosclerotic plaques
ABCA1 protein facilitates transfer of cholesterol–> converted cholesterol ester by LCAT
What is the fate of mature HDL?
Taken up by liver –> bile salts
Cells requiring additional cholesterol –> scavenger receptors (SR-B1)
Exchange cholesterol ester–> TAG with VLDL–> Cholesterol exchange transferase protein (CETP)
What is the function of each lipoprotein?
Chylomicrons –> dietary TAG intestines –> adipose tissue
VLDL –> TAG synthesised in liver –> adipose tissue
IDL–> Precursor of LDL, short lived, transport cholesterol synthesised in liver–> tissue
LDL –> Cholesterol liver–> tissue
HDL–> Excess cholesterol –> liver- bile salts or other cells- requiring cholesterol
What are hyperlipoproteinaemias?
Raised plasma levels of lipoproteins
Overproduction or under removal
What are the 6 main classes of hyperproteinaemias?
I–> Chylomicrons in fasting plasma–> defective lipoprotein lipase
IIa–> defective LDL receptor
IIb–> unknown
III–> raised IDL and chylomicron remnant–> rare (1 in 10000) –> defective apoE
IV–> unknown
V–> Raised chylomicrons and VLDL fasting plasma–> unknown
All coronary artery disease
What are the clinical signs of hypercholesterolaemia?
High levels of cholesterol
Depositions
Xanthelasma –> yellow patches on eyelids
Tendon Xanthoma –> nodule on tendons
Corneal arcus–> white circle around the eye –> common in older people
How does raised LDL causes atherosclerosis?
Oxidised LDL–> macrohages –> Foam cells –> accumulate in intima of BV–> Fatty streaks –> evlove into atherosclerotic plaque –> grows and enroaches on lumen (angina) –> ruptures –> thrombosis (activated platelets and clotting cascade) –> stroke or MI
How are hyperlipoproteinaemias treated?
Non-drug approach and drug approach
Non-drug approach
–> Diet –> reduce cholesterol, saturated lipids, increase fibre (bile salts sequestered by fibre stops bile being recycled ↑ secretion)
–> lifestyle –> increase exercise, stop smoking (oxidative stress)
Drugs
–> statins –> inhibits the HMG-CoA reductase
–> Bile Salt sequesterants –> Bind bile salts in GI tract–> liver produces more –> more cholesterol used
What is a cholesterol test?
Measure amount of cholesterol in blood
Total cholesterol <5mmol/L
Non HDL cholesterol <4mmol/L
LDL cholesterol <3mmol/L
HDL cholesterol men >1mmol/L, women >1.2mmol/L
Total cholesterol: HDL-C ratio above 6 considered high risk
Triacylglyceride <2mmol/L in fasted sample
