L4: Lipid Transport Flashcards by Elizabeth Watson

What are lipids?

Structurally diverse, insoluble molecules

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What are the different types of lipids?

Triacylglycerol (di and mono too)
Fatty acids
Cholesterol (cholesterol esters)
Phospholipids
Vitamins A, D, E and K

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What is the problem with transport?

Insoluble cant transport in blood
Solution–> carrier molecules
2% lipids (mainly FA) bound to albumin
98% –> lipoprotein particles

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What is the structure of a phospholipid?

Polar head (hydrophilic) –> classified according to this
Phosphate
Glycerol backbone
Non Polar tails (hydrophobic)- Fatty acids X2

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How can phospholipids arrange themselves?

Bilayer sheet
Liposome–> bilayer in a sphere shape
Micelle

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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

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How is cholesterol transported around the body?

Cholesterol esters

Esterification –> Lecithin Cholesterol Acyltransferase (LCAT) or Acyl-coenzyme A cholesterol acyltransferase

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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

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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)

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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

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How was the density off lipoproteins discovered?

Flotation Ultracentrifugation –> separated

Particle diameter inversely proportional to density

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What are apoplipoproteins?

Associated proteins

Lipoprotein specific

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How many classes of apoplipoproteins are there?

6 major –> A, B, C, D, E and H

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What are the most important apoplipoproteins?

apoB (VLDL, IDL, LDL) and apoAI (HDL)

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What is the function of apoplipoproteins?

Structural role–> packaging of water insoluble lipids
Functional role–> Co-factor for enzymes
–> ligands for cell surface receptors

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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