Week 12 - Unit 3 Flashcards
Cholesterol can come from both the diet and is synthesized in the body. True or false?
True
True or False:
the majority of cholesterol in the body is form dietary sources.
False- most is from endogenous synthesis
Cholesterol is used as a membrane sterol and is the precursor for all ______ ______.
Steroid hormones
Cholesterol is transported in ______ in the body.
Lipoproteins
Dietary cholesterol is transported in ______.
chylomicrons
Cholesterol is synthesized in the _____ (but most tissues can synthesis it if needed) and packaged into _____ particles.
Liver (primary)
VLDL
VLDL particles mature to ______ particles, that are taken up by cells via the ____ ______.
LDL
LDL receptor
Cholesterol is transported from peripheral tissues back to the liver via _____ particles.
HDL
What three levels is cholesterol synthesis regulated at ?
Phosphorylation
Transcription
Feed-back inhibition
Statins are cholesterol reducing drugs that target the regulatory enzyme ______.
HMG CoA reductase
Cholesterol has a ring structure with a _____ group on the ___ carbon, this allows it to be amphipathic (can insert into membrane).
Hydroxyl
3 carbon
Cholesterol is a ______ (shape)molecule and can influence the _____ of the cell membrane when inserted.
planar
fluidity
Approx how much cholesterol in the body is in the free form ?
1/3
What happens to the other 2/3 of the cholesterol in the body that is not in free form?
It is Esterified
-FA added with ester bond to the OH on the 3 carbon of Cholesterol
What does esterification of cholesterol do ?
keeps the cholesterol within the cell and out of the cell membrane (means of storage)
Creation of Cholesterol needs a lot of energy and is provided in the form of _____.
NADPH
Synthesis of Cholesterol starts with condensation of 2 _____ to make ______.
Acetyl CoA (CoAsh is released)
Acetoacetyl CoA
What is the intermediate generated in the first steps of cholesterol synthesis?
Mevalonate
In synthesis of Cholesterol, what does Acetoacetyl CoA condense combine with to make beta-hydroxy-beta-methyl glutaryl CoA (HMG-CoA)
Acetyl CoA (CoASH is released)
Where does Cholesterol synthesis take place?
Where does ketone synthesis take place?
Cytosol
Mitochondria
What is the regulatory enzyme for Cholesterol synthesis in the first steps involving Acetyl CoA to form intermediate Mevalonate?
HMG-CoA reductase
Where is HMG-CoA reductase?
describe its physical features?
ER membrane
8 Transmembrane domains
What does HMG-CoA reductase in the ER membrane use for energy?
2NADPH+2H
and release of CoASh
What level is HMG-CoA reductase regulated at ?
Transcriptional level (highly regulated)
When Cholesterol levels are high , it binds ______ and the receptor ______ that is next to the one it binds forming a transcription factor family complex in the ER
SCAP (sterol response element binding protein cleavage activating protein)
SREBP (sterol response element binding protein)
-Transcription factor family complex
As Cholesterol levels drop, it is released from SCAP in the ER, and SCAP and SREBP move to the membrane of _______.
Golgi
In the golgi, after the transcription factors have moved into the membrane during low cholesterol levels, there is a cleavage reaction that releases the _________ from _____ that is facilitated by ______ _______.
DNA-binding domain
SREBP
2 Proteases (S1P and S2P)
The DNA binding domain for SCAP+SREBP will translocate to the _______ once cleaved from the golgi.
nucleus
Once in the nucleus, the SCAP+SREBP DNA-binding domain will bind the ________ ______ ______.
This will then ……..
Sterol response element (Regulatory element) SRE
then regulate gene transcription to increase production of HMG-CoA reductase in the cell when Cholesterol levels are low
HMG-CoA Reductase is also impacted/regulated by high levels of _____ in the cell.
Sterols
High levels of Sterols will target ______ ______ in the ER membrane for proteolysis and degradation in the cell (decreases the synthesis of cholesterol).
HMG-CoA reductase (control by degredation)
HMG-CoA reductase is also controlled by phosphorylation, under high levels of insuling, the _______ is activated and will _______ it making it active.
Phosphatase
dephosphorylate
What will inactivate the HMG-CoA reductase (through covalent modification)?
High levels of :
AMP, Glucagon, Sterols
-all activate the AMP-activated protein kinase to phosphorylate and inactivate the HMG-CoA reductase
From the starting point of Mevalonate (cholesterol synthesis intermediate), there are _____ reactions adding _____ _____ groups.
3
3 phosphate groups
What is the purpose of the phosphate transfers (adding 3 groups) to mevalonate?
to activate Carbon 5 and Carbon 3
The phosphate group from Carbon 3 and the Carbonyl group from the end are removed to create a ______ ______ . This intermediate that is created will be the first of two necessary Isoprenes .
Double bond
What is the first necessary Isoprene created called how is it made?
1 Phosphate group and CO2 removed from :
3-phospho 5-pyrophosphate mevalonate
Name: Isopentenyl pyrophosphate (5 C) - synthetic precursor for cholesterol synthesis
Isopentenyl pyrophosphate is isomerized to __________
Dimethylallyl pyrophosphate (5C) (synthetic precursor for cholesterol synthesis)
What is the first step involving the two precursors to cholesterol?
condensation of:
Dimethylallyl pyrophosphate
Isopentenyl pyrophosphate
(release of 2 Pi and there is a total 2 Pi left on the new compound)
What is the new compound created when Demethylallyl pyrophosphate and Isopentenyl pyrophosphate are condensed and 2 Pi is released?
Geranyl pyrophosphate (10C- intermediate)
What is added to the Geranyl pyrophosphate (10C) to make the 15C substance in Cholesterol synthesis?
Isopentenyl pyrophosphate (5C) -one Pi is released
What is the 15C intermediate in Cholesterol synthesis called after Isopentenyl pyrophosphate is added to Geranyl pyrophosphate ?
Farnesyl pyrophosphate
What is the next reaction after Farnesyl pyrophosphate (15C) is created?
2 Farnesyl pyrophosphates are condensed to create:
Squalene (30C intermediate)
-2 PPi released
-NADPH is used and leaves NADP+
Why are Geranyl pyrophosphate and Farnesyl pyrophosphate important for reasons besides cholesterol synthesis?
They can both be used to attach to proteins to change their function (similar to phosphorylation)
What happens to the 30C Squalene molecule in cholesterol synthesis?
Oxygenated by enzyme:
Squalene monooxygenase
-NADPH is used and NADP+ released
-O2 used and H2O released
What is created when Squalene (30C-intermediate) is acted on by Squalene monooxygenase, what is the product called? what feature does it have?
Squalene 2,3 epoxide
Epoxide ring (open ring with oxygen hanging off end)
The opening of the epoxide ring on Squalene 2,3 epoxide will facilitate cyclization into the first cyclic-intermediate called _______.
Lanosterol
What is Lanosterol used for ?
first foundational cyclic-intermediate
used to create Cholesterol (through many reactions)
Once synthesized in the cytosol, Cholesterol has many fates, one fate is the esterfication into Cholesterol Ester by ……..
what is the enzyme that carries this out ?
Fatty Acyl-CoA is added to Hydroxyl group (CoASH released)
Enzyme: ACAT (Acetyl CoA acyl-transferase)
Cholesterol ester is more ______ than regular cholesterol and are packaged into VLDL particles for transport to peripheral tissues.
Hydrophobic
In the synthesis of Cholesterol (hepatic) to Bile salts, the first step is the conversion of Cholesterol to what compound?
7-Alpha Hydroxycholesterol
What is added to a Carbon on Cholesterol to make 7-alpha-Hydroxycholesterol?
Hydroxyl group added to 7 carbon
What is the enzyme that will convert Cholesterol to 7alpha-hydroxycholesterol ?
what can inhibit the enzyme?
7-alpha hydroxylase (regulatory enzyme for pathway)
high levels of bile salts
When 7alpha-hydroxylase acts on Cholesterol, what will it need to make 7aplha-Hydroxycholesterol?
O2 + H+ (to provide the O, and then H2O is released)
NADPH reduces Cytochrome P450(Fe3+) to Cytochrome P450 (Fe2+) that can donate reduce the Cholesterol and donate the H needed to add an OH to cholesterol at the 7 carbon
The series of reductions, hydroxylation, and conversion of hydroxyls to Alpha of 7Alpha-Hydroxycholesterol will produce what two primary compounds?
Chenodeoxycholic acid (has 2 OH- groups)
Cholic Acid (has 3 OH- groups-additional on 12C)
—-Double bond in Beta ring has been reduced (gone) in both structures
The side chains of Chenodeoxycholic acid and Cholic acid are show as ionized (COO-) because the pKA is _____. So at a pH of ____ which is the pH in small intestine, 50% will be ionized and 50% will be protonated (example bile acid (ionized) vs bile salt)
6
6
Which form of Chenodeoxycholic Acid and Cholic Acid is more effective as a detergent?
the Ionized form (COO-) is more effective vs. the protonated form
To facilitate keeping the side chain of Bile Acids ionized, we can _________ bile acids with other compounds to ______ the pka of the side chain.
conjugate
reduce
What are the two main compounds that can be added to Cholic acid side chain (COO-) to reduce the pka of the side chain?
Taurine and Glycine
What is the name of the compound when Taurine is added to Cholic acid and what is the pka?
Taurocholic Acid
pKa = 2 (would be almost totally ionized at pKa 6 in intestine)
What is the name of the compound when Glycine is added to Cholic acid and what is the pKa?
Glycocholic acid
pKa = 4 (would be almost totally ionized at pKa 6 in intestine)
Lower pKa of the Bile acid molecules will _______ soluability and increase the _______ of fats during digestion.
increase
emulsification
Less than _____ of Bile salts are secreted in feces. They are considered secondary bile salts that are ______ and _______ by bacteria in gut.
5%
Deconjugate
Dehydroxylate
reduces solubility and makes difficult to be absorbed
What are the primary bile salts that are reabsorbed?
- Cholic acid
2. Chenodeoxycholic acid
What are the secondary bile salts (removal of OH from 7 Carbon in both and less soluble) that are less likely to be reabsorbed?
- Deoxycholic acid (OH removed on 7 C)
2. Lithocholic acid (OH removed on 7 and 12 C)
The secondary bile salts are mostly excreted in feces, and the ones that are recycled are not ________ but can be _________ to increase the solubility.
rehydroxylated (on Carbons)
Re-conjugated
HMGCoA reductase activity would be reduced if SREBP is bound to SCAP in the ER. True or False?
True - associated with high cholesterol so transcription is reduced
HMGCoA reductase activity would be reduced if elevated levels of sterols are in the cell. True or False?
True - keep activity low of enzyme, target the enzyme for degradation when sterols are high in cell
HMGCoA reductase activity would be reduced if it is phosphorylated by AMPK (AMP-kinase).
True or False?
True - only active if dephosphorylated
HMGCoA reductase activity would be reduced if there are elevated levels of insulin. True or False?
False- insulin will activate the phosphatase and increase the activity of the dephosphorylated HMG-CoA reductase
What are the 4 main transporters of Cholesterol in the body?
Chylomicrons
VLDL to IDL
LDL
HDL
What Apoproteins are associated with chylomicrons?
What happens after interaction with HDL?
- ApoB48 (marker)
- receive ApoCII and ApoE from interaction with HDL
- Hydrolyzes to FA+Glycerol
How is the Chylomicron recycled?
turns into Chylomicron remnant
- ApoE on the chylomicron will bind to ApoE receptor on Liver to uptake it and recycle
VLDL will primarily carry newly synthesized _____ and ______ (less) . The former is packaged into ___.
Fatty Acids (highest percent) and Cholesterol
TriacylGlycerols
What Apoproteins is VLDL associated with
ApoB100 (marker)
-interact with HDL - receive ApoCII and ApoE
What Apoprotein interacts with Lipoprotein lipase so FA can be freed and taken up by muscles and adipose?
ApoCII on the chylomicrons and VLDL
When VLDL reduces it ____ content it will mature into ______ .
Triacylglycerol
LDL
The LDL has a higher content of ______ than VLDL.
Cholesterol (up to 40 to 50%)
LDL is taken up by ______ ______ and is a way of transporting cholesterol from liver to tissues.
peripheral tissues
HDL are secreted as _____ lipoproteins from the liver, and their role is to interact with peripheral tissue and move _______ from tissue back to the liver.
Nascent
Cholesterol
What is name for HDL (High density lipoproteins) function?
Reverse Cholesterol transport
List the size of the Lipoproteins from largest to smallest?
Chylomicrons Chylomicron remnant VLDL IDL LDL HDL
Once VLDL has lost a large proportion of its TG, it is called an _____.
IDL (Intermediary Density Lipoprotein)
The VLDL will mature into IDL and go back to liver and is taken up via interaction with ______on IDL and the ______receptor on Liver
ApoE
The IDL can mature further into ______ through interaction with _________ in the blood.
LDL
HTGL ( Hepatic TriacylGlycerol Lipase) - lipase in the capillary walls - similar to LPL
The removal of more _____ by ______ on the IDL particles results in the maturation of the particle into _____.
TG
Hepatic Triacylglycerol lipase (HTGL)
LDL
LDL can be taken up by receptors on ____ and _____ tissue. This is how cholesterol is delivered to tissues in general.
liver
peripheral
LDL has the apoprotein ______ that is characteristic of it.
ApoB100
Excess LDL in pathological conditions will be _____ and will damage the vascular endothelial cells generating _________ ______ through the synthesis of foam cells.
oxidized
sclerotic plaque
LDL with apoB100 (primarily cholesterol ester) , is taken up by peripheral tissue through ________ _____ ______ .
Receptor-mediated endocytosis - vesicle pinches off and entire LDL and receptor are in the endosome in cell
The Receptor is _______ back to cell surface and the rest of the LDL core in the endosome is (cholesterol esters) is digested by _______ into what 3 things?
Recycled
Lysosomes
AA, FA, cholesterol
The receptor mediated endocytosis of LDL will be a way to regulate ________ ______ of cholesterol by increasing levels in the ER membrane of cells and binding the transcription factor complex to stop transcription.
endogenous synthesis
What three things will increasing levels of Cholesterol (sterols) do to HMG-CoA reductase when in the cell?
- Bind to the Transcription factor in ER (SCAP-SREBP) stopping endogenous transcription
- Increase HMG-CoA reductase degredation (proteolysis)
- Phosphorylate and inactivate HMG-CoA Reductase by increasing the activity of AMP-activated protein kinase
There are many characterized mutations in the LDL receptor gene including what sections: (6)
- Promoter
- Ligand binding
- EGF precursor homology domain
- Glycosylation regions
- Membrane domain
- Cytoplasmic domain
Many of the mutations in the LDL receptor gene cause what ?
Cholesterol to be elevated and pathological Hypercholesteremia in various family types
In the comparison lipid panels:
If patient A has 420mg Cholesterol and 158mg TG
If patient A has 314mg Cholesterol and 295 mg TG
What do they have?
A has hypercholesterol only -
B has Metabolic syndrome
If a patient has high Triacylglycerols, what is that reflective of ?
chylomicrons n/a (fasting labwork)- and cleared rapidly so rare to cause disturbance in TG levels
only levels of circulating VLDL
If a patient has high Cholesterol level, what is this reflective of ?
elevated LDL particles
chylomicrons n/a in fasting labwork
What three ways can HDL originate?
- From liver as nascent particles
- Budding off of VLDL or chylomicrons
- Accumulation of phospholipids around an ApoA protein
(somewhat empty sack)
HDL contain very ______ levels of TG and Cholesterol.
Low
HDL moves ________ from _______rich cells back to the liver. HDL particles gain their contents from the _______ tissues.
cholesterol
Cholesterol
peripheral
HDL can exchange ______ and ______ with other lipoproteins.
Apoproteins
Lipids
HDL contains apoproteins _____ ______ , and ______. And have a ______ layer phospholipid membrane.
ApoA 1 and 2 (characterizing element)
ApoCII
ApoE
Mono
One of the first roles of HDL is the transfer of ______ and ______ onto the Chylomicron and VLDL particles.
ApoCII (activates Lipoprotein lipase)
ApoE (required for re-uptake by the liver)
When HDL particles encounter tissues/cells with high levels of cholesterol, you will have cholesterol _______ from that cell into the HDL particle.
Efflux
The movement of cholesterol from the encountered tissues/cells into HDL is facilitated by the _______
ABCA transporters
- ATP binding cassette proteins - use ATP hydrolysis to move cholesterol from inner leaflet of membrane to outer leaflet of membrane where it can be moved into HDL particle
Once the cholesterol has been picked up by the HDL particle from tissues, it must be _______ in order for the HDL particle to retain it inside its membrane.
Esterified
The esterification of the Cholesterol in the HDL particle is performed by the enzyme ______
LCAT (lecithin cholesterol acyltranferase)
-similar to enzyme ACAT that is found inside the cell and performs the same action in the cell to esterify it to keep it inside the cell
The reaction by LCAT (lecithin cholesterol acyltransferase) is the removal what from Lecithin?
Placed where on the Cholesterol?
Fatty acid from C2 Carbon from Lecithin
Placed on Hydroxyl group on 3C of Cholesterol (end cap
makes cholesterol Ester)
What is Lecithin transformed into once LCAT (lecithin cholesterol acyltransferase) acts upon it to transfer a FA group to Cholesterol?
Lysolecithin
Once Cholesterol is esterified within the HDL particle and is in circulation, the other function is the transfer of ______ from HDL to ______. This is a means by which the TG can be transferred to HDL and Cholesterol Ester can be transferred to _____.
lipids
VLDL
VLDL
Transfer of Cholesterol ester from HDL to VLDL and the transfer of Triacylglycerols from VLDL to HDL is performed by the enzyme _______.
CETP (Cholesterol ester transferase protein)
-means of delivering cholesterol in higher concentrations back to the liver via the VLDL particle (first has to be matured to IDL and LDL then goes to liver)
HDL can be taken up by the liver and is done by the _______ receptor also know as the _____ receptor.
Scavenger receptor
SR1 receptor
Cholesterol is the precursor for ____ classes of ______.
5
Hormones
What are the 5 classes that cholesterol is the precursor for (hormones)?
- Glucocorticoids
- Mineralcorticoids
- Androgens
- Estrogens
- Progestogens
Hormones made from Cholesterol are hydrophobic and usually bound by _______ to travel through the blood.. Or to a specific carrier protein.
Albumin
Hormones made from cholesterol will either bind to cytosolic receptors or receptors in then nucleus, but in either case the receptors will travel and bind to DNA and regulate _______ ________.
gene transcription
Synthesis of Cortisol takes place in the _______ _____. It is initiated by the interaction of _______ binding ________.
Adrenal Cortex
ACTH …binding….G protein coupled receptor
In the synthesis of cortisol, the ______ have previously come into the cells and deposited Cholesterol ester.
LDL
The increasing cAMP activate _________ which then activates a ______ that cleaves Cholesterol into its free form away from the Cholesterol ester form.
Protein Kinase A
Lipase
The cholesterol once cleaved from its ester form, under goes a series of reactions in ____ and _____ and creates ______ that can then diffuse out of the cell.
Mitochondria
Endoplasmic Reticulum
Cortisol (will bind with albumin to circulate)
What 4 things can all contribute to an inflammatory state of the vascluar endothelium and lead to formation of a fatty streak ? (athlerosclerosis)
- Elevated LDL or reduced HDL
- Cigarette smoking
- Chronic hyperglycemia
- Elevated Angiotensin II
what is LDL oxidation ?
interaction of LDL with a reactive oxygen species that damages the LDL (can occur because any number of free radicals )
LDL oxidation can occur for the 4 reasons mentioned previously and under conditions of chronic elevated _____ and reduced _____.
LDL
HDL
Under harsh conditions (4 conditions listed previously), the entothelial cells will express receptors for inflammatory cells or _________, this allows them to move into the interstitial space between the ______ and _______ called the Intama.
Monocytes
endothelial layer
smooth muscle layer
At the same time the Monocytes move into the Intama through receptors, the Elevated ______ are small enough to pass through the endothelial cells and can get trapped, then oxidized and taken up by ______ and convert the Macrophage to a ______ ____.
LDL
Macrophages
Foam cell
What is a foam cell?
a Macrophage laden with oxidized LDLs and in the intama (space between the endothelial cells and smooth muscle cells of the vascular tissue)
The accumulation of foam cells will ________ the Endothelial cells and ______ the vasculature. This happens because the smooth muscle will try to patch over the foam cells as they accumulate and forma core.
Dystend
Acclue
The core that has accumulated the foam cells and the smooth muscle cells tried to patch will eventually become necrotic, and eventually rupture and form a _________ that can completely or partially acclued the vesicle.
thrombosis
Statins will _______ _______ activity to control cholesterol. Reducing endogenous cholesterol synthesis.
Inhibit HMG-CoA reductase
Bile acid resins will ______ ______ ______ of bile salts. Inhibiting the normal reabsorbtion process of Bile salts into the liver.
increase fecal excretion
______can facilitate reducing cholesterol by activating ________ which will increase _______of VLDL particles.
Niacin
Lipoprotein lipase
Catabolism
________ can activate LPL by antagonizing the PPARalpha. This will help reduce the cholesterol levels in the blood.
Fibrates
_______ reduces intestinal absorption of free cholesterol from the gut lumen.
Ezetimibe (class of drugs)
