lipid transport and dyslipidaemia Flashcards
what are lipids made of
cholesterol and triglycerides
what roles do lipids play in the body
energy and stores
antioxidants
insulation and protection
hormones
how is fat absorbed from the diet
- Enters as droplets
- Emulsified by bile salts in intestine
- Pancreatic lipase breaks down micelles to monoglycerides and free fatty acids
- Monoglycerides and free fatty acids move into epithelial cells and reform triglycerides
- Chylomicrons are formed and they are transported into the blood
what are lipoproteins
Hydrophobic lipid core and hydrophilic polar phospholipid coating (apoproteins- bind to specific receptors on liver and other tissues)
what are the 5 types of lipoproteins
chylomicrons
VLDL - very low density
IDL - intermediate density
LDL- low density
HDL- high density
what are chylomicrons composed of
mainly lipids
apoproteins B48, A, C, E
what are VLDLs comprised of
mainly triglycerides
apoproteins B100, A, C, E
what are IDLs comprised of
50/50 fat and protein
apoproteins B100, E
what are LDLs comprised of
cholesterol
apoprotein B100
what are HDLs comprised of
protein
apoprotein A1, A11, C, E
what does apoprotein B48 do
in chylomicrons, for intestinal uptake of dietary lipids
what does apoprotein E do
in chylomicrons, mediates uptake of chylomicron remnants into liver by LDL receptor
what does apoprotein B100 do
in VLDL, IDL and LDL, main ligand for LDL receptor
what does apoprotein A1 do
in HDL, promotes cholesterol efflux from tissues to liver for excretion
what is the LDL receptor pathway
- LDL binds on liver hepatocytes
- Receptor mediated endocytosis
- Taken up into coated vesicles (pH 5)
- LDL disassociated from liver
- Vesicle pinches to separate receptor and LDL
- Vesicle with LDL fuses with lysosome - cholesterol release in cytosol
- Vesicle with receptor fuses with cell membrane - replaces LDL receptor
how are exogenous lipids moved around the body
- absorbed by ileum - moves to lymph, blood to muscle as chylomicrons
- TG hydrolysed by lipoprotein lipase to MG and FA
- remaining chylomicron remnants with cholesteryl esters endocytosed in liver
- cholesterol stores, oxides to bile acids or enters endogenous pathway
how are endogenous lipids moved around the body
- cholesterol and newly synthesised TG travel to adipose as VLDL
- TG hydrolysed by lipoprotein lipase
- VLDL is made smaller to LDLs
- bind to LDL receptors on cells and deposit cholesterol
what is reverse cholesterol transport
HDL removes cholesterol from cells and returns it to the liver
how does reverse cholesterol transport work
pre-beta HDL takes cholesterol from cells
LCAT esterifies pre-beta HDL containing cholesterol
transferred by cholesterol ester protein to the liver for excretion
what is ACAT
acyl CoA - cholesterol acyltransferase
- catalyses intracellular synthesis of cholesteryl ester in macrophages, adrenal cortex, gut and liver
what is LCAT
lethicin cholesterol acyltransferase
- catalyses cholesteryl ether synthesis in HDL particles
what is CETP
cholesteryl ester transfer protein
- Transfer of cholesteryl ester between HDL to IDL or VDL
what is PLTP
phospholipid transfer protein
- Transfer of cholesterol and TG between different classes of lipoprotein particles in plasma
what is PCSK9 and how does it affect cholesterol
- Binds to hepatic LDL receptors and promotes their lysosomal degradation
Prevents recycling of the LDL receptors back onto cell surface of hepatocytes - limits LDL uptake into the liver
what is dyslipidaemia
- Disorder of lipid metabolism including lipoprotein overproduction and deficiency
Major risk factor for coronary heart disease - directly related to cholesterol levels
dyslipidaemia epidemiology
60% adults TC >5mmol/L
western diet high in TC/LDL
aetiology of dyslipidaemia
primary - 60%
secondary - 40%
what are the causes of primary dyslipidaemia
genetics
- familial hypercholesteremia
- familial combined hyperlipidaemia
- hype 3 hyperlipidaemia
- polygenic hypercholesterolaemia
- primary hypertriglyceridemia
- lysosomal lipase deficiency
dietary and lifestyle
what causes secondary dyslipidaemia
- disease
- drugs
- age
- post menopause
how are atherosclerosis caused
injury in blood vessel
- smoking
- DM
- high cholesterol
- high BP
what are the steps in atherosclerosis
- injury in blood vessel
- adhesion molecules and monocytes migrate
- cholesterol deposited and oxidised
- foam cells migrate and stick
- plaque formation
- necrotic core and fibrous cap formation
what are the targets for lipid levels
nothing specific
TC <5mmol/L
LDL <3mmol/L
what is lipoprotein A
LDL species strongly associated with atherosclerosis
what 7 classes of drugs can be used for lowering lipid levels
statins
fibrates
cholesterol absorption inhibitors
bile acid binding resins
plant stanols/sterols
alirocumab
inclisiran
how do statins work for high lipid levels
competitive reversible HMGCoA reductase inhibitor - decreases cholesterol synthesis
how are statins metabolised
CYP450 and glucuronidation
how do statins affect the formation of atherosclerosis
increases collagen - plaque stability
decreases platelet aggregation
anti-oxidant
how do fibrates work
PPAR agonists - normally nuclear receptors that modulate lipid and carb metabolism
- increase lipoprotein lipase
what are cholesterol absorption inhibitors
nicotinic acid and ezetimibe
how does nicotinic acid work to reduce cholesterol
water soluble vit B
lowers LDL and TG by inhibiting synthesis
how does ezetimibe work
inhibits cholesterol absorption in intestine, conjugated to ezetimibe glucuronide and excreted in stools
how do bile acid binding resins work
- Bind to cholesterol and excretes it
- Can worsen symptoms
how do plant stanols and sterols work
decrease cholesterol - dietary and supplements
how do alirocumab and evolocumab work
inhibit PCSK9
how does inclisiran work
small interfering RNA that inhibits translation of PCSK9 mRNA
