Cholesterol and Lipid Metabolism Flashcards
describe the solubility of lipids
insoluble, or sparingly soluble, in water
what are lipids essential for?
membrane biogenesis
membrane integrity
what are the roles of lipids?
energy sources
precursors for hormones
signalling molecules
give two non polar lipids?
cholesterol esters
triglycerides
how are non polar lipids transported in the blood?
within lipoproteins
what are the types of lipoproteins?
high density lipoproteins (HDL)
low density lipoproteins (LDL)
very low density lipoprotein (VLDL)
chylomicrons
what is the difference in lipoproteins in people with CV disease?
elevated LDL (or particles rich in triglycerides) decreased HDL
what are the causes of the difference in lipoproteins in people with CV disease?
diet and lifestyle
genetic factors eg familial hypercholesterolaemia
what do lipoproteins consist of?
a hydrophobic core and a hydrophilic coat
describe the hydrophobic core of lipoproteins
contains esterified cholesterol and triglycerides
describe the hydrophilic coat of lipoproteins
a monolayer of amphipathic cholesterol, phospholipids and one, or more, apoproteins
which apoproteins do HDLs contain?
apoA1 and apoA2
which apoprotein do LDLs contain?
apoB-100
which apoprotein do VLDLs contain?
apoB-100
which apoprotein do chylomicrons contain?
apoB-48
what is the role of apo-B containing lipoproteins?
deliver triglycerides to muscle for ATP biogenesis and adipocytes for storage
where are chylomicrons formed?
intestinal cells
what is the role of chylomicrons?
transport dietary triglycerides
the exogenous pathway
where are VLDL particles formed?
liver cells
what is the role of VLDL particles?
to transport triglycerides synthesised in that organ
the endogenous pathway
summarise the life cycle of apo-B containing liposomes
assembly
intravascular metabolism (involving hydrolysis of the triglyceride core)
receptor mediated clearance
how are triglycerides in chylomicrons formed?
monoglycerides combine with free fatty acids
how are cholesteryl esters in chylomicrons formed?
cholesterol combines with NCPC1L protein and esterifies
how are chylomicrons assembled?
triglyceride combines with apoB48
MTP and lipidation are used
what is an enterocyte?
an intestinal cell
the site of chylomicron assembly
how do chylomicrons exit enterocytes?
by exocytosis following the addition of a second apoprotein (apoA1)
how are chylomicrons carried to the systemic circulation?
they enter the lymphatics and is crammed in lymph via the thoracic duct
what is MTP?
microsomal triglyceride transfer protein
where are the components that form chylomicrons derived from?
digestion of dietary fat and bile
where are the fatty acids that form VLDL particles derived from?
adipose tissue and de novo synthesis
describe the assembly of VLDL particles
MTP lipidates apoB100 forming nascent VLDL that coalesces with triglyceride droplets
how are chylomicrons and VLDL particles activated?
by the transfer of apoCII from HDL particles
what is lipoprotein lipase (LPL)?
a lipolytic enzyme associated with the endothelium of capillaries in adipose and muscle tissue
how are apoB containing lipoproteins metabolised?
ApoCII facilitates binding of the lipoproteins to LPL which hydrolysis core triglycerides to free fatty acids and glycerol which enters tissues
what are the particles depleted of triglycerides but still containing cholesteryl esters termed?
chylomicron and VLDL remnants
what is the role of LPL?
causes the particles to become relatively enriched in cholesterol due to triglyceride metabolism
what is apoE?
a high affinity ligand for receptor mediated clearance
what happens once the apoB containing lipoproteins dissociate from LPL?
apoCII is transferred to HDL particles in exchange for apoE
remnants return to the liver and are further metabolised by hepatic lipase
all apoB48 remnants and half apo100 remnants are cleared by receptor mediated endocytosis into hepatocytes
what happens to the remaining apoB100 containing remnants?
they lose further triglyceride through hepatic lipase, become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins become LDL particles lacking apoE and retaining solely apoB100
what is the clearance of LDL particles crucially dependant upon?
the LDL receptor expressed by the liver and other tissues
clearance by the liver is most important
how does cellular uptake of LDL particles occur?
receptor-mediated endocytosis
how is cholesterol released in the cell?
at the lysosome, it is released from choleryl ester by hydrolysis
what does released cholesterol cause?
inhibition of HMG-CoA reductase which is the rate limiting enzyme in de novo cholesterol synthesis
down regulation on LDL receptor expression
storage of cholesterol as cholesterol ester
why is LDL the bad cholesterol?
because at the start of atherosclerosis, LDL from the blood is uptaken into the intima of the artery and oxidised into atherogenic oxidised LDL
what initiates atherosclerosis?
dysfunction and injury of the lining of blood vessels
why is HDL the good cholesterol?
it plays a key role in removing excess cholesterol from cells by transporting it in plasma to the liver
only the liver has the ability to eliminate cholesterol from the body
where is HDL formed?
mainly in the liver
how is HDL formed?
initially as apoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (disc like pre-B-HDL)
this matures in the plasma to spherical a-HDL as surface cholesterol which is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle
how does HDL deliver cholesterol to the liver?
it accepts excess cholesterol from the plasma membrane of cells and transports it via transport cholesterol tranport
what happens once HDL reaches the liver?
it interacts with a receptor (scavenger receptor B1) that allows transfer of cholesterol and cholesteryl esters into hepatocytes
what does cholesterol ester transfer protein (CETP) do?
in the plasma it mediates the transfer of cholesteryl esters from HDL to VLDL and LDL, indirectly returning cholesterol to the liver
what is the classification system of primary dyslipidaemia?
Frederickson
what causes primary dislipidamia?
a combination of diet and genetic factors
what causes secondary dislipidaemia?
it is a consequence of other diseases eg type II diabetes, hypothyroidism, alcoholism, liver disease
name examples of statins
simvastatin and atorvastatin
how do statins reduce cholesterol?
act as competitive inhibitors of HMG-CoA reductase which is the 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
when are statins ineffective
in homozygous familial hypercholesterolaemia where LDL receptors are lacking
when are fibrates used?
in patients with very high triglyceride levels
name fibrates
bezafibrate
gemfibrozil
how do fibrates act?
they are agonists of a nuclear receptor (PPARalpha) which enhances the transcription of the gene that encodes for LPL
name bile acid binding resins
colestyramine
colestipol
colsevelam
how do bile binding resins act?
they cause the excretion of bile salts resulting in more cholesterol to be converted to bile salts by interrupting enterohepatic recycling
what do binding resins cause?
decreased absorption of triglycerides and increased LDL receptor expression
how does ezetimibe act?
it inhibits NPC1L1 transport protein in enterocytes of the duodenum, reducing the absorption of cholesterol
what does ezetimibe cause?
a decrease in LDL with little change in HDL
