Lipid transport Flashcards
lipids
- triacylglycerol, fatty acids, cholesterol, cholesterol esters, phospholipids, vitamin A D E K
- hydrophobic so insoluble in water so must be transported in plasma bound to carriers
- ~98% carried as lipoprotein particles
- ~2% (fatty acids) carried bound non-covalently to albumin but has a limited capacity ~3mmol/L
typical plasma lipid concentrations
- triacylglycerol 0-2 mmol/L
- phospholipids ~2.5 mmol/L
- total cholesterol <5 mmol/L
- cholesterol esters ~3.5 mmol/L
- free fatty acids 0.3-0.8 mmol/L
- total lipids 4000-8500 mg/L
phospholipids
- hydrophilic polar phospholipid head
- hydrophobic nonpolar fatty acid tails
- classified according to their polar head group
- forms liposomes, micelles and bilayer sheets
cholesterol
- some obtained from diet but mostly synthesised in liver
- essential component of membrane fluidity
- precursor of steroid hormones (cortisol, aldosterone, testosterone, oestrogen)
- precursor of bile acids
- transported around body as cholesterol ester
what are lipoprotein particles
- multi-molecular complexes containing variable amounts of different lipids in non-covalent (hydrophobic) association with specific proteins
- main function is to transport water-insoluble lipid molecules in bloodstream
what are apolipoproteins
- each class of lipoproteins has a particular complement of proteins
- six major classes (A, B, C, D, E, H)
- apoB and apoAI important
- can be integral or peripheral to phospholipid bilayer
- structural role: packaging water insoluble lipids as they have hydrophobic and hydrophilic regions
- functional roles: cofactor for enzymes and ligands for cell surface receptors
lipoprotein structure
surface coat
- phospholipid monolayer with cholesterol
- peripheral apolipoproteins (apoC, apoE)
- integral apolipoproteins (apoA, apoB)
hydrophobic core (cargo)
- triacylglycerols
- cholesterol esters
- fat soluble vitamins (A, D, E, K)
lipoprotein stability
- only stable if they maintain spherical shape
- dependent on ratio of core to surface lipids
- as lipid from hydrophobic core is removed and taken up by tissues, surface coat must also be reduced
classes of lipoproteins
- differ in relative amounts of type of lipids and apolipoprotein composition
- different physical properties like net electrical charge, size, molecular weight, density
- can be separated by electropheresis or flotation ultracentrifugation
what are the classes of lipoproteins and their functions
- chylomicrons transport dietary TAG from intestine to tissues
- VLDL transport TAG synthesised in liver to adipose tissue for storage
- IDL is a short-lived precursor for LDL and transports cholesterol synthesised in liver to tissues
- LDL transports cholesterol synthesised in liver to tissues
- HDL transports excess tissue cholesterol to liver for disposal as bile salts and to cells requiring additional cholesterol
lipoprotein particle sizes
particle diameter inversely proportional to density
bigchylomicron-VLDL-IDL-LDL-HDLsmall
lipoprotein lipase
- removes core TAGs from lipoprotein particles
- attached to endothelial surface of capillaries in adipose tissue and muscle
- hydrolyses TAGs in lipoproteins releasing fatty acids and glycerol
- requires apoC-II as cofactor
lipoprotein lipase
- removes core TAGs from lipoprotein particles
- attached to endothelial surface of capillaries in adipose tissue and muscle
- hydrolyses TAGs in lipoproteins releasing fatty acids and glycerol
- requires apoC-II as cofactor
LCAT (lecithin cholesterol acyltransferase)
- important in formation of lipoproteins and maintaining structure
- converts cholesterol to cholesterol ester using fatty acid derived from lecithin
- deficiency results in unstable lipoproteins of abnormal structure and failure of lipid transport
chylomicron metabolism
- fatty acids re-esterified to TAG using glycerol phosphate in small intestine epithelial cells
- TAGs packaged with other dietary lipids (fat, cholesterol, vitamins) into chylomicrons
- apoB-48 added to chylomicrons and released into lymphatic system
- enter bloodstream at thoracic duct which empties into left subclavian vein
- acquire apoC and apoE and carried to tissues
- lipoprotein lipase on capillary walls of muscle and adipose hydrolyses TAGs releasing fatty acids and glycerol (fatty acids converted to TAG for storage in adipose or utilised for energy in muscle and glycerol transported to liver)
- when TAG reduced to 20%, chylomicron becomes chylomicron remnant
- chylomicron remnants return to liver and bind to LDL receptor so taken up by receptor mediated endocytosis
- lysosomes release remaining contents for use in metabolism
VLDL metabolism
- VLDL particles made in liver to transport TAG to other tissues
- apoB100 added during formation and apoC + apoE added from HDL particles in blood
- VLDL binds to lipoprotein lipase (LPL) on capillary endothelial cells in muscle and adipose and starts to become depleted of TAG
IDL and LDL
- as TAG content of VLDL particles drops, some VLDL particles dissociate from LPL and return to liver
- if VLDL content depletes to ~30%, particle becomes short-lived IDL particle
- IDL can be taken up by liver or rebind LPL enzyme to further deplete TAG content
- if depletes to ~10% IDL loses apoC and apoE and become LDL particle (high cholesterol content)
function of LDL (bad cholesterol)
primary function to provide cholesterol from liver to peripheral tissues by receptor-mediated endocytosis where LDL particles taken up by cell and cholesterol released inside
how do LDL enter cells by receptor mediated endocytosis
- cells requiring cholesterol express specific LDL receptors on plasma membrane
- LDL receptors recognise and bind to apoB100 on LDL particles
- receptor/LDL complex taken into cell by endocytosis into endosomes
- fuse with lysosomes for digestion releasing cholesterol and fatty acids (cholesterol stored or used by cell)
- reduces synthesis of LDL receptors to prevent cell accumulating too much cholesterol
clinical relevance of LDL particles
- half-life of LDL in blood much longer than VLDL and IDL as they’re not efficiently taken up by liver due to absence of apoC and apoE (liver LDL receptors have high affinity for apoE)
- LDL more susceptible to **oxidative damage ** so can lead to formation of atherosclerotic plaques
familial hypercholesterolaemia
- absence (homozygous) or deficiency (heterozygous) of functional LDL receptors
- elevated levels of plasma LDL and cholesterol
- homozygotes develop extensive atherosclerosis early in life
familial hypercholesterolaemia
- absence (homozygous) or deficiency (heterozygous) of functional LDL receptors
- elevated levels of plasma LDL and cholesterol
- homozygotes develop extensive atherosclerosis early in life
HDL (good cholesterol) metabolism
nascent HDL synthesis
- nascent HDL particles with low TAG content synthesised by liver and intestine
- some HDL can bud off from chylomicrons and VLDL as they’re digested by LPL
- free apoA-I can acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent HDL
HDL maturation
- HDL particles have a hollow core that progressively fills as it accumulates phospholipids and cholesterol from cells lining blood vessels
- transfer of lipids to HDL doesn’t require enzyme activity
reverse cholesterol transport
- HDL removes cholesterol from cells with excess cholesterol and returns it to liver for disposal as bile salts
- important for blood vessels as it reduces likelihood of foam cells and atherosclerotic plaques
- ABCA1 protein within cell facilitates transfer of cholesterol to HDL
- cholesterol then coverted to cholesterol ester by LCAT
fate of mature HDL
- mature HDL taken up by liver via specific receptors
- cells requiring additional cholesterol (steroidogenic cells) can utilise scavenger receptor SR-B1 to obtain cholesterol from HDL
- HDL can exchange cholesterol ester for TAG with VLDL particles via CETP
what are dyslipoproteinaemias
- any defect in the metabolism of plasma lipoproteins
- primary - familial inborn error of lipoprotein metabolism
- secondary - acquired as a result of diet, drugs or underlying disease
