cholesterol fxn in membranes
provides order, rigidity
cholesterol fxn in liver
precursor of the bile salts which emulsify and digest fats
cholesterol fxn in endocrine tissues
precursor of steroid hormones, e.g. glucocorticoids, mineralocorticoids, sex hormones, vitamin D
what is cholesterol synthesized from?
so all nutrients - glucose, fatty acids, amino acids, alc - provide C atoms for cholesterol biosynthesis
where is cholesterol synthesized
but liver is most active organ
what is the structure of cholesterol
hydrophobic sterol ring structure
where in the cell does cholesterol synthesis occur
cytosol and endoplasmic reticulum
how do statin drugs work?
they inhibit the rate-limiting enzyme of cholesterol biosynthesis, HMGCoA reductase
these lower cholesterol levels
describe biosynthesis of cholesterol
1. 2 acetyl CoA -> acetoaceyl CoA + Acetyl CoA via Thiolase
2. HMGCoA REDUCTASE reaction, rate limiting, makes this into HMGCoA
uses 2 NADPHs
3. Mevalonate is metabolized in 2 steps to isopentyl pyrophosphate
4. Isopentyl pyrophosphate ultimately produces choelsterol
what can isopentyl pyrophosphate produce
dolichol, which is in membraen glycolipids
vitamins E and A
what makes HMGCoA?
1) made in liver mito from 3 acetyl CoA by a specific HMGCoA synthase for ketogenesis
2) made in cytosol of most cells by another isoform for cholesterol and isoprene units
what activates HMGCoA reductases activity?
dephosphorylated state (-OH) = activated state
transcriptionally activated by insulin activation, via increase in SREBP2 or protein-phosphatase 1, and thus dephosphorylation
also increased in low levels of cholesterol states
what deactivates HMGCoA reductase activity?
-OP (phosphorylated) is inactive form of enzyme
1. glucagon and epi, via phosphorylation
2. AMP kinase
3. end product inhibition by cholesterol, which decreases processing of SREBP and increases ubiquitination of HMGCoA R and increases proteosomal degradation
how does high cholesterol impact HMGCoA Reductase activity
1) it inhibits transcription of the HMGCoA reductase gene by preventing the processing and nuclear translocation of the txn factor SREBP-1, which binds to the sterol regulatory element of the HMGCoA reductase gene & activates it when cholesterol and otehr sterols are low
2) promotes degredation of HMGCoA reductase enznyme (decreases the half-life)
how does low cholesterol impact HMGCoA reductase activity
1) when cholesterol is low, SREBP-1 is a txn factor that binds to sterol regulatory element of HMGCoA R gene, activates it. and SREBP-1 is activated by insulin.
2) low cholesterol elevates synthesis of HMGCoAR by not downregulating HMGCoAR transcription or stability
function of LDL
transports high amounts of cholesterol and cholesterol esters in the blood
how does LDL receptor work
cholesterol binds to LDL receptors
receptor-mediated endocytosis occurs
lysosomal degredation of the choelsterol
what's the impact of high levels of intracellular cholesterol on LDL receptor?
downregulates LDL receptor synthesis
this lowers the entry of LDLs / LDL-derived cholesterol into cells
what do mutations in the LDL receptor cause
1) atherosclerosis, because circulating LDLs are not efficienctly removed from the blood
so serum cholesterol levels are high
2) accumulated LDLs in blood are subjected to oxidation of their phospholipids by oxygen radicals, produce oxidized LDLs, which macrophages engulf, and results in formation of foam cells
what are foam cells? what do they cause?
macrophages that mistakenly engulf oxidized LDL receptors because they recognize them as oxygen radicals
foam cells clog endothelial space of blood vessels, produce fatty streaks and atherosclerotic plaques
besides statins, what treatments can lower cholesterol?
1) statins inhibit HMGCoA R
2) limitation of certain foods - liver, meats
3) cholestyramine, a postively-charged bile salt binding resin, lowers the reabsorption of bile salts and pushes liver to synthesize more bile salts from cholesterol, thus lowering cholesterol levels
why is HDL / LDL "good" / "bad" cholesterol
physicians test HDL/LDL levels to estimate risk of atherosclerosis
HDL transport cholesterol from blood to liver for metabolism
LDL contain high amounts of cholesterol
where are chylomicrons produced?
what is their function?
what do they contain?
produced in GI tract
carry triglycerides to liver & adipose, NOT much cholesterol
where is VLDL produced?
what is its function?
what does it contain?
produced in liver
packages excess FA made in liver into triglycerides for delivery in blood, esp. to adipose to store
contains mainly triglyceides, some cholesterol
where are intermediate density lipoproteins produced? what is their function? what do they contain?
produced in blood from VLDL
function is endocytosed by liver or converted to LDL
contain high cholesterol, intermediate triglycerides
where is HDL produced? function? contains?
produced in liver and intestine
returns cholesterol from peripheral tissue to liver
is raised by Vitamin B Niacin and moderate alcohol consumption
consists of apolipoprotein A, C, E, high in protein, low in triglycerides / cholesterol
where is LDL produced?
what does it contain?
produced in blood, as end product of VLDL metabolism
1) taken up into cell via LDL receptor mediated endocytosis, then lysosomal digestion, then cholesterol released
2) high levels of intracellular cholesterol DOWNREGULATE LDL receptor synthesis
3) many mutations of LDL receptor occur -> atherosclerosis
4) LDL accumulated in blood can be targeted by oxygen radicals -> oxidized LDLs
5) oxidized LDLs recognized by macrophages, when they accumulate, macrophages -> foam cells which clog endothelial space -> plaques
contain: apolipoprotein B, high in cholesterol and their esters