lipid synthesis: cholesterol Flashcards
list 5 things cholesterol is important for (showing that it’s not always a bad thing)
- component of cell membranes
- precursor to steroid hormones
- helps make bile salts
- helps synthesize NTs
- helps synthesize vitamin D3
T or F: we can make our own cholesterol
true! we don’t actually require it in our diet
where does most cholesterol synthesis occur
in the liver
how many carbons is cholesterol
27
where do the 27C of cholesterol come from
all from acetyl-CoA
how many carbons is acetyl-coa
2
______ produce intermediates between acetate (acetyl-CoA) and cholesterol
isoprene units
how many carbons in one isoprene unit
5
how are isoprenes activated
by the addition of one or more P
in what three forms is cholesterol mostly exported from the liver
steroid hormones, bile acids, vitamin D
list the 4 basic steps of cholesterol synthesis
- make mevalonate from acetyl-CoAs
- make an activated isoprene unit from mevalonate
- condense 6 activated isoprenes together to make 30C linear squalene
- make squalene cyclical and remove a couple methyl groups to make cholesterol
what is the first step to making mevalonate
acetyl CoA + acetyl CoA = acetoacetyl-CoA
acetoacetyl-CoA + acetyl-CoA = HMG-CoA (6C)
once HMG-CoA is made from 3 acetyl-CoAs, how is mevalonate made
HMG-CoA is reduced to mevalonate (NADPH as the electron donor)
which step of mevalonate synthesis is the commitment step
the reduction of HMG-CoA to mevalonate
which enzyme reduces HMG-CoA to mevalonate (NADPH is the electron donor)
HMG-CoA reductase
once mevalonate is made, what is the next step in cholesterol synthesis
making activated isoprene units from mevalonate
describe how active isoprene units are made from mevalonate
3 phosphates from separate ATPs are transferred to mevalonate
T or F: when making isoprene units from mevalonate, the three needed phosphates come from one ATP
false! each phosphate comes from a DIFFERENT ATP
what is the next step in isoprene synthesis when we have mevalonate-P-P-P
the molecule is decarboxylated and one P leaves
how many carbons is mevalonate
6
after mevalonate-P-P-P is decarboxylated and one P has left, what molecule do we have
a 5C activated isoprene (5C-P-P)
during cholesterol synthesis, what is the next step once we have an activated isoprene (5C-P-P)
condense 6 isoprenes to make squalene
how many carbons is squalene
30
in squalene synthesis, in what configuration are the isoprenes attached to each other
head to tail
what is the “head” of the isoprene unit
the pyrophosphate end
what is the “tail” of the isoprene unit
the 5C unit
describe the events that occur when two isoprenes are condensed to form a 10C molecule
one of the two pyrophosphate sets is displaced
during isoprene condensation, what is the 10C-P-P intermediate called
geranyl pyrophosphate (10C-P-P)
describe the events that occur when the 10C-P-P (geranyl pyrophosphate) molecule is condensed with another 5C isoprene unit
one of the pyrophosphate sets is displaced = 15C-P-P molecule
during isoprene condensation, what is the 15C-P-P intermediate called
farnesyl pyrophosphate
during isoprene condensation, what is the next step once we have made 15C-P-P (farnesyl pyrophosphate)
we join to of those molecules together to get squalene
(15C-P-P + 15C-P-P)
during squalene synthesis, how are the two 15C-P-P molecules joined (what configuration)
head to head! (NOT head to tail)
what happens to the phosphates when 15C-P-P is added to 15C-P-P
all 4 phosphates are lost
T or F: squalene has 4 phosphates
false; it has no phosphates. All of them were lost during the head to head condensation of 15C-P-P + 15C-P-P
is squalene linear or circular
linear
is cholesterol linear or circular
circular
what still needs to be done to convert squalene to cholesterol (3)
close off the 4 rings, reduce the double bonds in the alkyl chain, add a hydroxyl
what is the first step of making cholesterol from squalene
a monooxygenase adds one oxygen of O2 to make an epoxide. The other oxygen gets reduced to water
during cholesterol synthesis from squalene, what occurs once an epoxide has been made
the epoxide can then be cyclized via a cyclase
during cholesterol synthesis from squalene, what molecule is made once the epoxide is cyclized via a cyclase
lanosterol
T or F: lanosterol is found in both plants and animals
false; lanosterol is in animals only
since plants lack lanosterol, describe what their cholesterol pathway looks like
the pathway will diverge before cyclization can occur
at what point in the squalene –> cholesterol pathway does it diverge between animals and plants? (ie which molecule is it)
squalene 2,3-epoxide
in the plant squalene -> cholesterol pathway, what are the products (instead of lanosterol)
stigmasterol and ergosterol
in the animal squalene -> cholesterol pathway, what happens once lanosterol has been produced
it’s then converted to cholesterol in 20+ minor steps that move around the methyl groups
are the derivatives of cholesterol more or less polar than cholesterol
more polar!
are the derivatives of cholesterol more or less hydrophobic than cholesterol
less hydrophobic!
list 4 less hydrophobic derivatives of cholesterol
hydroxysterols, bile salts, steroid hormones, vitamin D
list 1 derivative of cholesterol that is more hydrophobic than cholesterol
cholesteryl ester
what is a cholesteryl ester
a cholesterol bound to a FA
how many ATP were needed to make one cholesterol molecule
18
describe why 18 ATP were needed to make 1 cholesterol molecule
3 needed to make each mevalonate-P-P-P (which leads to one isoprene), but we need 6 isoprene = 3x6 = 18 total ATP
T or F: cholesterol is broken down in animal cells
false! it cannot be catabolized in animal cells!
since cholesterol cannot be broken down in animal cells, where does excess cholesterol go?
it must be excreted
which step of cholesterol synthesis is regulated
HMG-CoA –> mevalonate (the commitment step)
what hormone activates HMG-CoA reductase? how?
insulin. reversible phosphorylation
what hormone inactivates HMG-CoA reductase? how
glucagon. reversible phosphorylation
other than insulin and glucagon, what enzyme regulates HMG-CoA reductase. how?
AMP kinase. reversible phosphorylation
does AMP kinase activate or inactivate HMG-CoA reductase
inactivate
when does AMP kinase inactivate HMG-CoA reductase? why?
when ATP levels are low. This is because cholesterol synthesis uses lots of ATP
T or F: high blood cholesterol increases risk of heart attack and stroke
true
____ are a common group of drugs that lower blood cholesterol levels
Statins
describe how statins lower blood cholesterol levels. which step do they act at?
they inhibit HMG-CoA reductase by binding and blocking the active site during the HMG-CoA –> mevalonate step
other then preventing cholesterol synthesis, what benefit can statins have
they encourage less tumor growth
describe how statins can prevent tumor growth
RAS is a protein found overexpressed/overactive in tumors, and it’s attached to an isoprene derived lipid (15C-P-P). by taking statins, we get less isoprenes = less functional RAS = less tumor growth
T or F: A negative feedback loop regulates HMG-CoA reductase gene expression based on dietary intake of cholesterol
true
HMG-CoA reductase gene expression depends on which family of proteins
sterol regulatory element binding proteins (SREBPs)
what does SREBP stand for
sterol regulatory element binding protein
when first synthesized, where does SREBP embed
in the ER membrane
describe the activities in the ER membrane when cholesterol levels are high
sterols bind to Insig and SREBP cleavage activating protein (SCAP) in the ER membrane. Sterol-bound Insig acts like an anchor and keeps SCAP-SREBP in the ER
describe the activities in the ER membrane when cholesterol levels are low
sterols can no longer bind to Insig, so the anchor is degraded. SCAP then shuttles SREBP to the golgi membrane to be cleaved by proteases. A portion of the cleaved SREBP leaves the golgi into the nucleus to act as a TF to enhance gene expression of sterol synthesizing enzymes = increase in cholesterol synthesis
in what form do cholesterol and cholesteryl esters travel through the blood
as lipoproteins
what type of carrier proteins do lipoproteins have
apolipoproteins
describe the structure of lipoproteins
they have carrier proteins (apolipoproteins) along with their huge stash of lipids + they have a single layer of outer phospholipids
list the 4 classes of lipoproteins
chylomicrons, VLDL, LDL, HDL
what is heavier: protein or lipid
protein
if a lipoprotein has more lipid in regards to protein, does it have a high or low density
low density
what are apolipoproteins recognized by in order for them to help target specific classes of lipoproteins to specific tissues
recognized by cell surface receptors
list the 4 main pathways of lipoprotein movement
exogenous, enterhepatic, endogenous, reverse cholesterol transport pathway
which lipoprotein is the least dense? it has the most of what type of molecule
chylomicrons = least dense. They have the most TAGs (lipids)
briefly, what does the exogenous pathway do to chylomicrons
brings them from the small intestine to release free cholesterol in the liver
where in the body are chylomicrons generated
cells of the small intestine
where in the cells of the small intestine are chylomicrons generated
in the ER
from the small intestine, where do chylomicrons go (exogenous pathway)
they enter the lymphatic system
from the lymphatic system in the exogenous pathway, where do chylomicrons go
to the blood stream
from the bloodstream, what do chylomicrons do (exogenous pathway) + where has the bloodstream taken them
the apolipoprotein portion activates lipases in the capillaries of adipose, heart, mammary tissue, and also skeletal muscles
after apolipoproteins have activated lipases in adipose/heart/mammary/skeletal muscle tissues, what happens? (exogenous pathway)
free FAs are released from TAGs in these tissues
in the exogenous pathway, once free FAs have been released from TAGs in the heart/adipose/mammary/skeletal muscle tissue, in what state is chylomicron in?
the chylomicron remnants are now depleted of TAGs, but they’re still carrying dietary cholesterol
in the exogenous pathway, what happens to chylomicrons once they’re depleted of TAGs but still carry dietary cholesterol?
chylomicron remnants travel to the liver
what happens to chylomicron remnants in the liver?
they’re endocytosed and degraded by lysosomes
what is the result once chylomicrons are endocytosed and degraded by lysosomes in the liver?
dietary cholesterol is now free in the liver
T or F: all the dietary cholesterol in the liver (from the exogenous pathway) will be used
false; some will be used by membranes/building derivatives, but some will be excess
briefly, what does the enterohepatic pathway do
converts some liver cholesterol into bile salts in peroxisomes
where are bile salts stored
gallbladder
where will bile salts be secreted
into the small intestine
what do bile salts do in the small intestine
they emulsify fats
what does it mean to emulsify fats
to make the fats into smaller droplets
T or F: emulsification involves the breaking of bonds
false; no bonds are broken, but the fats are made into smaller droplets
after emulsifying fats, what are the two fates of bile salts
they can be reabsorbed into the liver or removed from the body with feces
briefly, what is the purpose of the endogenous pathway
excess dietary FAs/cholesterol in the liver are packaged into TAGs or cholesteryl esters + put into VLDL (excess cholesterol in liver goes to other tissues to be stored)
from the liver, where do VLDL go? (endogenous pathwat)
they travel through the bloodstream to muscle and adipose tissue
what happens to VLDL in muscle/adipose tissue (endogenous pathway)
apolipoproteins stimulate lipoprotein lipase activity and free FAs are released into these tissues
what happens to the density of VLDL when they lose some free FAs into muscle/adipose tissue (endogenous pathway)
it raises the density
what happens to VLDL when the density increases (endogenous pathway)
VLDL –> LDL
what do adipocytes do with the newly acquired free FAs from VLDL? (endogenous pathway)
they convert them to TAGs in lipid droplets for storage
what do muscle cells do with the newly acquired free FAs from VLDL? (endogenous pathway)
they oxidize them immediately to produce energy (in a fast)
each LDL has about ____ cholesteryl esters
1500
each LDL has about ___ molecules of cholesterol
500
in the endogenous pathway, what happens to LDL once it has converted from VLDL
it will now deposit cholesterol into tissues
which cells have LDL receptors on their PM (3)
muscle, adipose, and macrophages
for the cells that have LDL receptors on their PM, what will they do to LDL? (endogenous pathway)
they’re mediate cholesterol uptake from LDL, leaving LDL without cholesterol (note: it’s already also depleted of FA)
after LDL has dropped off its cholesterol into tissues, what happens (endogenous pathway)
it goes back to the liver
what happens to depleted LDL when it arrives at the liver (endogenous pathway)
LDL receptors on hepatocyte PM mediate reuptake of the entire LDL
what part of LDL is recognized by liver PM LDL receptors (endogenous pathway)
ApoB protein
describe the steps of receptor mediated endocytosis into a liver cell
LDL binds to a receptor which initiates endocytosis into the liver cell. LDL and its receptor enters the cell in an endosome, the portions of the endosome containing the receptor bud off and return to the PM. The rest of the endosome fuses with the lysosome where enzymes hydrolyze cholesteryl esters to release cholesterol + free FAs into the cytosol. ApoB is also degraded to amino acids
in what structure does an LDL and its receptor enter a cell
an endosome
once an LDL and its receptor have entered a cell in an endosome, what does that endosome fuse with
a lysosome
once an endosome containing LDL and its receptor have fused with a lysosome, what happens?
enzymes hydrolyze cholesteryl esters to release cholesterol and free FAs into the cytosol
what is ApoB degraded into
amino acids
what mutation do people with hypercholesterolemia have
mutations in the LDL receptor that prevents normal uptake of LDL particles in the liver
results of having hypercholesterolemia?
high blood cholesterol levels, higher risk of developing atherosclerosis plaques, cholesterol deposits in weird places (elbows, knees, cornea), coronary events in childhood
briefly, what does the reverse cholesterol pathway do
removes excess cholesterol from peripheral tissues and brings them to the liver
in the reverse cholesterol pathway, where do HDL originate?
the liver
in the reverse cholesterol pathway, describe the composition of the HDL particles that originate in the liver (think lipid and protein content)
HDL in the liver are protein rich. They have little cholesterol, no cholesteryl esters, and no TAGs
in the reverse cholesterol pathway, what enzyme do HDL contain
LCAT
in the reverse cholesterol pathway, what does LCAT do
generates cholesteryl esters from cholesterol and phosphatidylcholine
in the reverse cholesterol pathway, where on HDL is LCAT located
surface
in the reverse cholesterol pathway, where in the body would LCAT be working
in the blood + peripheral tissues
T or F: in the reverse cholesterol pathway, HDL can also pick up cholesteryl esters from peripheral tissues (meaning it doesn’t only rely on LCAT)
true
in the reverse cholesterol pathway, describe how HDL picks up cholesteryl esters from peripheral tissues
Picks it up from macrophages
in the reverse cholesterol pathway, where does HDL take all the excess cholesterol it’s picked up from peripheral tissues + LCAT activity
to the liver
in the reverse cholesterol pathway, describe what happens upon HDL returning to the liver (how does it drop off its cholesterol)
HDL apolipoproteins will bind to receptors on the PM, but the whole particle is NOT endocytosed. Instead, cholesterol and other lipids will selectively enter the liver
T or F: in the reverse cholesterol pathway, the entire HDL is endocytosed into the liver
false; cholesterol and other lipids will selectively enter
in the reverse cholesterol pathway, what happens to HDL once it’s returned the cholesterol to the liver
HDL dissociates from liver cells and can recirculate in the blood to collect more cholesteryl esters
what are plaques? what do they cause?
they’re accumulations of cholesterol that obstruct blood vessels and cause atherosclerosis, or lead to heart attack/stroke
how does HDL affect plaques
depleted HDL can pick up cholesterol at nascent plaques and return it to the liver (this depletes plaques)
are LDL good or bad when it comes to plaque formation
bad! they can undergo a few steps that lead to plaque formation
describe the events that LDL can undergo that lead to plaque formation
LDL can adhere to the ECM of epithelial cells that line arteries. WBCs will be attracted to these regions and uptake mass amounts of LDL until they become foam cells. These foam cells will eventually undergo apoptosis, and the remnants will contribute to a developing plaque
is LCAT + reverse cholesterol transport good or bad when it comes to plaques? explain
good! they can pick up some of the cholesterol in a growing plaque and return it to the liver, slowing plaque growth
list some things that might increase your HDL:LDL ratio
taking a statin, eating omega 3’s, maintaining healthy weight, exercise, stopping smoking, eating foods with red/purple pigments, taking niacin (B3) supplements
