cholesterol and lipid transport Flashcards
what leads to atherosclerosis
precipitation of cholesterol and other lipids in arteries
plaque formation pathway
damaged endothelial cells provide sites for accumulation of fats -> fatty streaks signal for recruitment of immune cells -> macrophages eat cholesterol and turn into foam cells in the plaque -> smooth muscle cells grow in the plaque generating fibrous cap -> plaque reduces blood flow -> necrosis at core can cause plaque rupture and thrombus formation
what is cholesterol
a steroid lipid that helps to regulate cell membrane fluidity; synthesized by cells and dietry intake
2 functions of cholesterol
- precursor to steroid hormone and bile salts;
- increases cell membrane fluidity
why do fats need to be transported correctly though the body
they are highly hydrophobic and so can precipitate in blood vessels forming plaques
what is cholesterol solubility at 30C
1/3million
how are lipids transported safely around the body
in lipoprotein carriers -phospholipid shell with a hydrophobic lipid core (cholesterol, triglycerides)
what part of the lipoprotein vessel dictates where the particle goes
the receptor targeting, hydrophilic apolipoprotein domain
what happens to the lipid:apolipoprotein ratio as it is transported around the body
ratio changes throughout the body, cholesterol is always transported from low to high density lipoprotein particles
where is the major source of cholesterol from in the body
the diet - eggs, fatty food, kidney, liver prawns
role of bile salts in cholesterol digestion
acts as a detergent to assist in the absorption of insoluble cholesterol from the intestine
what happens to cholesterol prior to it being packed for transport
it is esterefied to increase solubility
cholesterol-bile salt complex -> esterification
what are chylomicrons
large triglyceride-rich lipoproteins produced in enterocytes from dietary lipids ->transport vessels
cholesterol -> bile salt pathway (9)
- chylomicrons taken up from intestine;
- used in muscle/adipose;
- chylomicron remnant generated, transported to liver;
- V-LDL (very low desnity) formed in liver, transported back to muscle/adipose for use;
- IDL (intermediate density) in blood;
- transformed into LDL;
- used in numerous tissues via LDL receptor;
- picked up from tissue by HDL;
- transported to the liver to become bile salts
“good” vs “bad” cholesterol
bad - LDL, it is a measure of cholesterol headed to the tissues;
good - HDL , it is a measure of cholesterol headed to liver for excretion via bile salts
what are the desired cholesterol levels
LDL - <70-130mg/dL (lower numbers are better);
HDL - >40-60mg/dL (high numbers are better);
total cholesterol <200mg/dL;
triglycerides 10-150mg/dL (low better);
what to cholesterol therapies aim to do
reduce LDL levels
what is familial hypercholesterolema
a genetic disease characterised by high cholesterol and LDL in blood
familial hypercholesterolema inheritance pattern
autosomal dominant
heterozygote vs homozygote phenotype for familial hypercholesterolema
hetero - premature CVD at age 30-40;
homo - severe childhood CVD
familial hypercholesterolema symptoms (3)
- xanthoma;
- yellowish lipid deposits in eyelids;
- lumpy deposits in the tendons of the hands, elbow, knees etc.
healthy cells vs familial hypercholesterolema cells LDL uptake
healthy - healthy cells must have a receptor for LDL that allows it to be taken up from the plasma;
FH - the receptor must be defective causing them to have high plasma LDL;
where is the LDL receptor gene
chromosome 19
what is the familial hypercholesterolema mutation
single base bair mutation on C19 - tyrosine replaced with cysteine
statins MOA (important)
inhibit the enzyme HMG-CoA-reductase which catalyses the rate limiting step in cholesterol synthesis -> this decreases the intracellular cholesterol conc, causing SREBPs to promote expression of LDLR (and HMG-CoA reductase) genes and thus increase uptake of LDL from the blood => blood cholesterol levels fall
inhibits HMG-CoA -> mevalonic acid
HMG-CoA negative feedback system
HMG-CoA-reductase gene expression is inhibited by the product of its activity i.e. cholesterol
what is the SREBP pathway
sterol regulatory element binding proteins (SREBP) are transcription factors that bind to the sterol regularoty element (SRE) and promote gene expression for HMG-CoA-reductase
how does cholesterol regulate SREBP
high intracellular cholesterol keeps SREBP in the cytoplasm (thus downregulate expression of the gene) -> when cholesterol is low, SREBP mover to the nucleus to stimulate expression
what genes does SREBP switch on when in the nucleus (2)
HMG-CoA-reductase; LDL receptor
where in the body is cholesterol not damaging
when it is in the cells
when might statins be ineffective at reducing blood cholesterol levels
if dietry intake is excessive - cells may become saturated
a mutation in what intestinal receptor can increase uptake of cholesterol from the diet
Neimann-Pick C1-like 1 (NPC1L1)
how does benecol (and other plant steroids) work
competitively competes with cholesterol for transporter binding
what is ezetimibe
a drug which acts to block NPC1L1 -> may be given along side statins in cholesterol management
what mutation do pts with tangier disease have and what does this mean
ABCA1 (extrudes cholesterole from cells allowing it to become HDL) -> cannot make HDL and so have high LDL levels in the blood
why might PCSK9 protein be targeted in cholesterol treatment
PCSK9 binds to LDLRs and degrades them => reduction in these will result in an increase in LDLRs
