Lipid Transport Flashcards
Cholesterol
“good” and “bad” refers to lipoproteins
Cells that make steroid hormones need more cholesterol
- some obtained from diet but most in synthesised by the liver
- essential for membranes (modulates fluidity) and is a precursor of steroid hormones (cortisol, aldosterone, testosterone, oestrogen), precursor of bile acids
- transported around the body as bile salts (enzyme LCAT)
Lipoproteins
- spherical
- phospholipid mono layer with small amounts of cholesterol
- peripheral apolipoproteins (apoC, apoE) on top of the mono layer
- integral apolipoproteins (apoA, apoB) in the mono layer
Cargo consists of - TAG
- cholesterol esters
- fat soluble vitamins ADEK
Classes of lipoproteins
Chylomicrons - mainly TAG - from intestine to adipose VLDL - mainly TAG - liver to adipose IDL - sort lived intermediate - mainly cholesterol ester LDL - mainly cholesterol ester - from liver to tissues HDL - mainly protein and cholesterol ester - from tissues to liver h PARTICLE DIAMETER IS INVERSELY PROPORTIONAL TO DENSITY DENSITY OBTAINED BT FLOTATION ULTRACENTRIFUGATION
Apolipoproteins
apoB (VLDL, IDL and LDL) and apoA (HDL) are important
- are structural - packaging water insoluble lipid
- are functional - cofactors for enzymes and ligands for cell surface receptors
Chylomicron metabolism (transports lipids from small intestine to adipose and liver)
- loaded in the small intestine and apoB-58 added before entering the lymphatic system
- travel to the thoracic duct - empties into the left subclavian vein (bypasses liver on fist circulation) - acquire apoC and apoE once in blood
- apoC binds to lipoprotein lipase (attached to endothelial cells in capillaries) on adipocyte X and muscle - released FA enter cells depleting chylomicrons of its fat content
- when TAG reduced to ~20% apoC dissociates and becomes a chylomicron remnant
- chylomicron remnants return to the liver
- LDL receptor on hepacytes binds apoE and chylomicron remnant taken up by receptor mediated endocytosis
- lysosomes release remaining contents for use in metabolism
VLDL metabolism
- made in liver to transport TAG to other tissues
- apoB100 added during the formation of apoC and apoE added from HDL particles in blood
- VLDL binds to LPL on endothelial cells in adipose and muscle
- in muscle the released FA are used for energy production
- in adipose the FA are used for resyntheisis of TAG and stored as fat
IDL & LDL metabolism
Formation VLDL –>IDL –> LDL
- as TAG content of VLDL drops some dissociate from the LPL enzyme and return to the liver
- VLDL content depleted to ~30% the particle becomes a short lived IDL particle which can be taken up by the liver or rewind to LPL enzyme to further deplete in TAG content
- upon depletion to ~10% IDL loses apoC and apoE and become an LDL particle (high cholesterol content)
LDL metabolism
- provided cholesterol from liver to peripheral tissues (express an LDL receptor and take up LDL via receptor mediated endocytosis)
LDL does not have apoC or apoE so are not efficiently cleared by the liver
CLINICAL RELEVANCE - half life of LDL in blood is much longer that VLDL and IDL - so they are more susceptible to oxidative damage
- oxidised LDL taken up by macrophages that can transform to foam cells and contribute to the formation of atherosclerotic plaques
LDL entering cells
- cells requiring cholesterol express LDL receptors on plasma membrane
- apoB100 on LDL acts as a ligand
- receptor/LDL complex taken into cell by endocytosis into endosomes
- fuse with lysosomes for digestion to release cholesterol and fatty acids
- LDL-R expression controlled by cholesterol concentration in cell
HDL metabolism
Nascent HDL synthesised by the liver
HDL particles can bud off from chylomicrons and VLDL as they are digested by LPL
Maturation - nascent HDL accumulate phospholipid and cholesterol from cells lining blood vessels
- hollow core progressively fills and particle takes on a more globular shape
- transfer of lipids to HDL does not require enzyme activity
HDL metabolism 2
HDL can remove cholesterol-laden cells and return it to the liver (important for blood vessels as it reduces the likelihood of foam cells and atherosclerotic plaque formation
ABCA1 protein facilitates transfer of cholesterol to HDL, cholesterol converted to cholesterol ester by LCAT
MATURE HDL
- taken up by liver by specific receptors
- cells requiring additional cholesterol can utilise scavenger receptor to obtain cholesterol from HDL
- HDL can exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein CETP
Hyperlipoproteinaemia
Raised plasma levels of one or more lipoprotein classes from either over production or under removal due to defects in enzymes, receptors or apolipoproteins
Clinical signs
- high levels of cholesterol in the blood - depositions in various areas of the body
- xanthelasma - yellow patches on the eyelids
- tendon xanthoma - nodules on tendon
- corneal arcus - White circle around the eye (common in older people not released to cholesterol)
TREATMENT
- diet and lifestyle - fibre interferes with reabsorption of cholesterol in bile salts
- statins - reduces cholesterol sunny thesis by inhibiting HMG-CoA reductase
- bile salts sequestrants - binds bile salts in the GI tract - forces liver to produce more using more cholesterol
Raised sebum LDL
Associated with atherosclerosis - can rupture and trigger thrombosis which can lead to myocardial infarction it stroke
Plaque formation
Oxidised LDL builds up in the vascular smooth muscle - plaque expands and encroaches on the lumen reducing its size
Plaque ruptures - thrombosis
Cholesterol blood test
Total cholesterol:HDL-C ratio
The lower the ratio the better
Above size is considered a high risk of cardiovascular disease
