Lipid Metabolism Flashcards
describe lipids
insoluble, or sparingly soluble, in water
essential for membrane biogenesis and membrane integrity
energy sources, precursors for hormones and signaling molecules
describe non-polar lipids
e.g. cholesterol esters and triglycerides
transported in blood within lipoproteins (e.g. high density lipoprotein (HDL), low density lipoprotein (LDL))
cardiovascular disease (atheroscelrosis) is strongly associated with;
elevated LDL (or particles rich in triacylclylcerols; TAGs)
decreased HDL
causes include;
diet and lifestyle
genetic factors (e.g. familial hypercholesteroalaemia)
describe lipoproteins
microscopic spherical particles
hydrophobic core containing esterified cholesterol and triacylglycerols (TAGs)
hydrophilic coat compromising a monolayer of amphipathic cholesterol, phospholipids and one, or more, apoproteins (apo)
apoproteins are recognised by receptors in liver and other tissues allowing lipoproteins to bind cells
describe 4 major classes of lipoprotein
differ in size, relative proportions of core lipids and associated apoproteins;
HDL particles (contain apoA-I and apoA-II)
LDL particles (contain apoB-100)
very low density lipoprotein (VLDL) particles (contain apoB-100)
chylomicrons (contain apoB-48)
describe apoB-containing lipoproteins
deliver TAGs to muscle for ATP biogenesis and adipocytes for storage
chylomicrons are formed in intestinal cells and transport dietary triglycerides - exogenous pathway
VLDL particles are formed in liver cells and transport TAGs synthesised by that organ - endogenous pathway
life cycle;
assembly, with apoB-100 in liver and apoB-48 in intestine
intravascular metabolism (involving hydrolysis of TAG core)
receptor mediated clearance
describe the assembly of apoB-containing lipoproteins - chylomicrons
refer PP
describe the assembly of apoB-containing lipoproteins - VLDL particles
VLDL particles containing TAGs (and some cholesterylesters) are assembled in liver hepatocytes from free fatty acids
MTP lipidates apoB-100 forming nascent VLDL that coalesces with TAG droplets
describe activation of chylomicrons and VLDL particles
to target TAG delivery to adipose and muscle tissue, chylomicrons and VLDL particles must be activated by the trasnfer of apoV-II from HDL particles
describe intravascular metabolism of apoB-containing lipoproteins
lipoprotein lipase (LPL) - lipolytic enzyme associated with the endothelium of capillaries in adipose and muscle tissue
ApoC-II faciliates binding of chylomicrons and VLDL particles to LPL
LPL hydrolyses core TAGs to free fatty acids and glycerol which enter tissues
particles depleted of triglycerides (but still containing cholesteryl esters) are termed chylomicron and VLDL remnants
describe clearance of apoB-containing lipoproteins
LPL causes chylomicrons and VLDL particles to become relatively enriched in cholesteryl esters due to TAG metabolism
chylomicrons and VLDL dissociate from LPL
ApoC-II is transferred to back to HDL particles in exchange for apoE which is a high affinity ligand for receptor mediated clearance
particles are now remnants
remnants return to liver and are further metabolised by hepatic lipase
all chylomicron remnants and 50% of VLDL remnants are cleared by receptor-mediated endocytosis into hepatocytes
remaining VLDL remnants lose further TAG through hepatic lipase, become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins (IDL) become LDL particles lacking apoE and retaining solely apoB-100
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clearance of LDL particles is crucially dependant on nLDL receptor (apoB/E receptor) expressed by liver and other tissues
clearance by liver is most important
cellular uptake of LDL particles occurs via receptor mediated endocytosis
within the cell at the lysosome, cholesterol is released from cholesteryl ester by hydrolysis
released cholesterol;
inhibits HMG-CoA reductase which is the rate limiting enzyme in de novo cholesterol synthesis
down regulates LDL receptor expression
may be stored as cholesterol ester or used as a precursor for bile salt synthesis
describe LDL as ‘bad’ cholesterol
athersclerosis is focal disease of large and medium sized arteries
initiated by dysfunction and injury of the lining (endothelium) of blood vessels (risk factors include diabetes, high BP, smoking)
disease progression involves;
1. Uptake of LDL from the blood into the intima of the artery. LDL subsequently oxidized to atherogenic oxidised LDL (OXLDL)
2. Migration of monocytes (white blood cell) across the endothelium into the intima where they become macrophages
3. Uptake of OXLDL by macrophages (using scavenger receptors) converts them to cholesterol-laden foam cells that form a fatty streak (an early event in atherogenesis)
4. Release of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intima and the deposition of collagen
5. The formation of an atheromatous plaque consisting of a lipid core (product of dead foam cells) and a fibrous cap (smooth muscle cells and connective tissue)
describe HDL as ‘good’ cholesterol
key role in removing excess cholesterol from cells by transporting it in plasma to the liver
only the liver has the capacity to eliminate cholesterol from the body (as cholesterol secreted into bile, or used to synthesise bile salts)
HDL is formed mainly in the liver, initially as apoA-I association with small amount of surface phospholipid and unesterified cholesterol (pre-beta-HDL)
Disc-like pre-beta-HDL matures in the plasma to spherical alpha-HDL as surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle
Mature HDL accepts excess cholesterol from the plasma membrane of cells (e.g. macrophages) and delivers cholesterol to the liver, known as reverse cholesterol transport, by several mechanisms;
HDL reaching the liver interacts with a receptor (scavenger receptor-B1, SR-B1) that allows transfer of cholesterol and cholesteryl esters into hepatocytes
in the plasma, cholesterol ester transfer protein (CETP) mediates transfer of cholesteryl esters from HDL to VLDL and LDL, indirectly returning cholesterol to the liver
describe lipid-lowering drugs - statins
e.g. simvastatin and atorvastatin
drug of choice to reduce LDL - very effective in reducing total and LDL cholesterol (up to 60%) decreased TGAs (up to 40%) and modestly increase HDL (About 10%0
Act as competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase - rate limiting step in cholesterol synthesis in hepatocytes
Decrease in hepatocyte cholesterol synthesis causes a compensatory increase in LDL receptor expression and enhanced clearance of LDL (note: statins are ineffective in homozygous familial hypercholesterolaemia where LDL receptors are absent)
Other beneficial effects of statins include;
decreased inflammation
reversal of endothelial dysfunction
decreased thrombosis
stabilisation of atherosclerotic plaques
Administered orally at night
Adverse effects are few but include myositis and rarely rhabdomyolosis incidence of which is increased if statin is combined with a fibrate
describe lipid-lowering drugs - fibrates
Cause a pronounced decrease in TGAs (up to 50%) and modest decreases (up to 15%) and increases (up to 20%) in LDL and HDL, respectively. Examples are bezafibrate and gemfibrozil
First line drugs in patients with very high TGA levels
Act as agonists of a nuclear receptor (PPARalpha) to enhance the transcription of several genes, including that encoding LPL
Have few adverse effects, but like statins may rarely cause myositis – combination with latter is generally inadvisable. Best avoided in alcoholics who are predisposed to hypertriglyceridaemias, but also rhabdomyolosis
Incidence of other adverse effects (G.I. symptoms, pruritus and rash) greater than for statins
describe drugs that inhibit cholesterol absorption
Bile acid binding resins (colestyramine, colestipol, colsevelam) cause the excretion of bile salts resulting in more cholesterol to be converted to bile salts by interrupting enterohepatic recycling
ingested orally, not absorbed from GI tract, prevent the reabsorption of bile salts (which is normally virtually all)
binding resins cause;
decreased absorption of TGAs
increased LDL receptor expression
adverse effect is GI irritation
