what is the equation for total cholesterol?
TC = HDL + LDL + TG/5
what is the point of lipoproteins?
transport lipids and cholesterol through the body
where are the lipoproteins made that transport lipids, (TGs,FAs)? where are they sent?
chylomicrons are made in the intestine for general tissue use, VLDLs are made in the liver for general tissue use, and FA/albumin combinations are produced in the adipose tissue for muscle and the liver to use
what carries cholesterol to tissues?
VLDLs, LDLs (bad)
what carries cholesterol to the liver?
HDL (good)
what do lipoproteins consist of?
apoproteins, (either peripheral or integral), amphipathic lipids, (phospholipids, cholesterol), and nonpolar lipids, (cholesterol esters, triglycerides -> form the core)
what does apoliprotein, (apoprotein), A-I do?
receptor ligand for HDL, made in liver, used as indicator for HDL levels, activates PCAT/LCAT
where is Apo B-100?
on VLDL, IDL, LDL, (how LDL gets back into cell)
where is Apo B-48?
on chylomicrons
what is Apo C-II?
activates lipoprotein lipase
what is Apo C-III?
inhibits lipoprotein lipase, also blocks Apo E from re-entering the liver
what is Apo E?
ligand for the liver receptor that allows the chylomicron remnants to come back into the liver
what do Apo B100 and Apo B48 have in common?
they encoded by the same gene, however Apo B100 has a longer portion which is RNA edited out in the intestine in making Apo B48 by a deaminase not found in the liver
what is the first thing that happens to chylomicrons recently packed with TGs in the enterocyte when they enter the bloodstream?
they are created in the small intestine with Apo B48, but when they get to the bloodstream they pick up ApoC-II and Apo E from HDLs
after chylomicrons pick up pick up ApoC and Apo E from HDLs, what do they do?
the go through the bloodstream until they get to lipoprotein lipases which find the TGs and break them down, bringing the FAs into the fat or muscle
as chylomicrons go through the capillaries from lipoprotein lipase to lipoprotein lipase what happens?
they eventually have little TGs left and have more cholesterol/cholesterol ester, around this point, they give back Apo C-II, (don’t need it anymore, all TGs are gone)
when the chylomicrons give up Apo C-II, do they give up Apo E?
no they keep Apo E, which the liver has a receptor for. they dock at the liver and give up their contents, including cholesterols which can be used to make bile salts or VLDLs
when the liver sends out VLDLS, what apoprotein does it put on them? what happens when they hit the bloodstream?
Apo B100. Apo C and E are added by HDLs, and they go the lipoprotein lipases, which take about half the triglycerides
which has more TGs, chylomicrons or VLDLs?
when VLDLs lose about half their TGs, what are they considered? what about when they lose even more?
intermediate density lipoproteins, and then low density lipoproteins
once VLDLs have become LDLs, what happens to them?
they give back Apo E and C, and can go to the liver or any tissue in the body that has LDL receptors for use of the cholesterols
what do LDL receptors recognize? how are they brought into cells?
Apo B100 is recgonized, the LDLs are brought in by receptor mediated endocytosis and the resulting endosome is met with a lysosome that breaks down the protein, releasing the amino acids, free fatty acids and cholesterol, (can be used for cell membranes)
how does the cell store cholesterol?
the cell stores cholesterol as cholesterol esters
how does the cell make cholesterol esters for storage?
the ACAT rxn: cholesterol + fatty acid CoA = cholesterol ester, which is catalyzed by acyl CoA-cholesterol transferase
where are HDLs synthesized? what are they composed of?
in the liver and gut. they are made of mostly protein and some lipid.
what is the functino of HDL?
HDL transfers Apo C-II and Apo E to VLDL and chylomicrons
what is the first step for HDL formation?
the liver sends Apo-A1 to any peripheral tissue, where it interacts with ATP binding cassette, (ABCA), and a nascent HDL is released, made of cholesterols in pancake shape, (due to the amphipathic nature of the cholesterols).
how does the pancake shape of the nascent HDLs change?
first, VLDLs give HDLs phopholipids. then Apo-A1 stimulates PCAT activity, (phosphatidylcholine cholesterol acyl transferase), which takes a fatty acid from phosphatidylcholine and makes a cholesterol ester. this enzyme is found inside HDL
what is the point of making cholesterol esters in the nascent HDLs via the PCAT reaction?
cholesterol esters are non-polar, (unlike amphipathic cholesterols), and can fill the interior of HDLs like a ballon rather than a flat lipid bilayered pancake
do HDLs interact with the liver?
yes, they can “sweep by” and drop off some of their contents, or dock and drop off some of their contents
other than contributing the cholesterols that first form HDLs, what else does the ABCA, (ATP binding cassette) do?
it can put more cholesterol out on the surface for HDLs to pick up as well as bile and drugs
what is CETP?
cholesterol ester transfer protein, allows cholesterol esters to be transfered from VLDL to HDL in exchange for TGs
where do chylomicron remnants go?
the liver takes them up, makes bile salts out of them or repackage them as VLDL
how does the liver send out ApoA1?
as just the protein with a little bit of lipid around it
can the body make cholesterol?
yes, the liver can make it from scratch, (de-novo), as can other tissues
where does extra cholesterol go?
excreted through the gut
what does the synthesis of cholesterol start with? what happens to them? is this step regulated?
an acetyl CoA and an Acetoacetl CoA,(an acetyl CoA x2). HMG CoA sythase converts them to HMG CoA in a nonregulatory step
other than cholesterol, what other compound starts from HMG CoA?
ketone bodies are also made from HMG CoA, this is why the step to make it is not regulated.
where are ketone bodies made? where is cholesterol made?
ketone bodies are made in the mitochondria, cholesterol is made in the cytosol
what happens to HMG CoA in cholesterol synthesis? is this step regulated?
HMG CoA reductase begins its conversion to cholesterol, and this is the regulatory step, which is inhibited by cholesterol, (product), and also is the step targeted by statins
how is the HMG CoA reductase enzyme regulated in cholesterol synthesis in terms of gene transcription?
with high levels of cholesterol, cholesterol will bind to the SRE binding protien in the ER, where a DNA binding domain is sequestered. however if levels of cholesterol drop, then it will cease to bind to the SRE binding protein, causing the DNA binding domain to be released, & bind to the cell’s DNA and transcribe more HMG CoA reductase
how does will low levels of cholesterol affect HMG reductase?
it will induce more of the enzyme to be made
how do high levels of cholesterol affect the presence of HMG reductase?
high levels of sterols, including cholesterol will activate proteolysis of HMG CoA reductase
how does glucagon affect the activity of HMG reductase?
glucagon activates an AMP-activated protein kinase which phosphorylates HMG reductase INACTIVATING IT. this process is also activated by the presence of sterols and AMP as well as glucagon
how is the phosphorylated HMG CoA reductase made active again?
if the level of sterols, AMP drop, or the level of insulin rises, then a phosphatase will dephosphorylate HMG CoA reductase, which will then be ACTIVATED
how can coronary artery/heart disease, atherosclerosis start?
LDLs have to squeeze through blood vessel walls to get to the tissues beyond them, but sometimes while outside the blood vessels, these LDLs can become oxidized, which keeps them stuck outside. monocyctes come in response, become macrophages and consume the oxidized LDLs, becoming foam cells which have receptors for LDL/oxidized LDL and can exacerbate the forming plaque
what are some things that encourage oxidation of LDLs? what helps LDLs to remain non-oxidized?
superoxide, nitric oxide, nitrogen peroxide all can oxidize LDLs. vitamin E, ascorbic acid, (vit C), beta carotene can help prevent oxidation
what is lipoprotein (a)?
found on LDLs in different concentrations depending on genetics, they can compete with plasminogen, (anti-clot enzyme) binding sites w/out participating in the same function, (potenially bad).
what is a sd-LDL?
LDL which moves out of the bloodstream easier, though it has less of an affinity for the LDL receptor, therefore it can remain in the extracellular matrix longer -> more atherogenic.
what sympotoms of metabolic syndrome does a pt have to have 3 of to be considered at higher risk?
abdominal adiposity, (pear shape), high TGs, low HDLs, HTN, fasting hyperglycemia, (heading->diabetes), inflammatory signs, (albumin in the urine-> poorly functioning kidney)
what is a VAP test?
vertical auto profile which measures LP(a), LDL density, (A or B), HDL 2 or 3, (2 is more protective)
what are the postive, (bad), risk factors for CHD, (coronary heart disease)? are there negative, (good) risk factors?
age, (male 45+, female 55+), fam hx of CHD, smoking, HTN, HDL<35, diabetes, obesity are all risk factors for CHD. however, an 60+ HDL is a negative, (good), risk factor for CHD
how does risk factor level correlate with LDL target level?
CHD risk factors up to 1, LDL<160
CHD risk factors up to 2, LDL<130
anything higher, LDL should be at or below 100, (with angina maybe <70)
how can LDL be regulated? what are examples?
start with lifestyle changes then drug therapy. lifestyle changes include, lower total fat, (esp sat and trans), increase fiber, lower cholesterol, control weight, stress levels, excercise, quit smoking
what physiological/environmental factors can contribute to hyperlipidemia?
smoking, high TGs, (due to high fat diet, obesity), HTN, (stress, Na+, meds), homocysteine levels, (decreased Vit B12/folate)
how would a familial deficiency in LPL affect plasma LP and plasma lipids?
chylomicrons and TGs would be increased
how would an familial high level of blood cholesterol affect plasma LP and plasma lipids?
LDL and blood cholesterol would be increased
how would a familial combined hyperlipidemia affect plasma LP and plasma lipids?
VLDL, LDL, TGs, and cholesterol would be increased
how would a familial dysbetalipoproteinamia affect plasma LP and plasma lipids?
increased IDL, chylo remnants, TGs and cholesterol
how would a familial hyperTGemia affect plasma LP and plasma lipids?
increase in chylomicrons, VLDLs and TGs
how can cholesterol be treated with an rx targeting bile salts?
bile acid sequestrants can disallow bile-acid-cholesterols from rentry into the liver, and forced to be excreted through the gut
how can cholesterol be treated with an rx targeting HMG CoA reductase?
statins can inhibit HMG CoA reductase, tissues stop making cholesterol, this increases expression of LDL receptors, which brings in more LDLs from circulation, lowering the amount in the blood
how can cholesterol be treated with a nicotinic acid/niacin rx?
nicotinic acid/niacin, (N- part of NADH), blocks HDL uptake by liver, (keeps it in circulation longer), lowers TG mobilization, which decreases VLDL and LDL synthesis
what is a possible side effect of bile acid sequestrants?
what is a possible side effect of niacin rx?
jittery feeling
how can cholesterol be treated with a fibric acid rx?
fibric acid/fibrase suppresses Apo CIII, (inhibits lipoprotein lipase), -> this increases the function of LPL, which decreases TGs and increases HDLs. Apo CIII also blocks Apo E from docking at the liver, so suppression of it allows the chylo remnants to go into the liver.
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