LECTURE 21 - CHOLESTEROL Flashcards
what are the building blocks of cholesterol?
made by assembly of isoprene subunits
what is the starting material for the synthesis of cholesterol?
Acetyl CoA
what is the mevalonate pathway and the key regulatory pathway
acetyl CoA is converted to HMG-CoA (until now it’s the same as ketogenesis)
HMG-CoA is made into mevalonate by HMG-CoA reductase (key regulatory enzyme)
this enzyme uses 2NADPH (makes 2 NADP)
how is mevalonate made into squalene?
needs 3 investments of ATP and one NADPH investment
this pathway needs a lot of ATP
farnesyl pyrophosphate (right before squalene) is a lipid anchor in membranes
how is a farnesyl anchor made?
made by prenylation, add prenyls to the protein to anchor it to the membrane
used to anchor to non rafts
what does the synthesis of cholesterol need?
requires 36 ATP and 16 NADPH per cholesterol
why is cholesterol not degraded?
very precious, a lot of energy is invested into this, so you don’t want to degrade it
what are the two levels of regulation of cholesterol?
body and cell
in the body, the input needs to be the same as the output from excretion
cholesterol is excreted from bile
what are the two ways that HMG-CoA is regulated?
- energy state (you need enough energy to do this)
- gene regulation (sensing the concentration of cholesterol)
how is HMG-CoA regulated by the energy state?
if there is a high AMP to ATP ratio, this means there is a low energy state
AMP activates AMPK, which will phosphorylate HMG-CoA reductase and inactivate it
protein phosphatase can reactivate HMG-CoA when the energy state is high enough
how is HMG-CoA reductase and LDL-R controlled by gene regulation?
this all depends on the concentration of cholesterol in the ER
in the ER membrane, Scap has a cholesterol sensing domain
when it does not sense cholesterol, Scap transports SREBP from the ER to the GA
in the GA, a site 1 protease (S1P) cleaves SREBP at site 1 and releases the bHLH domain, which is further processed by S2P
this bHLH goes into the nucleus and binds on the promoter and activates the target gene
this increases transcription of HMG-CoA-reductase and LDL-R
when there are high levels of cholesterol, the protein remains in the ER, there is no transport and no activation of the gene
what is the function of cholesterol esters and how are they made in different locations?
the function is storage
in the intestine (chylomicron), liver (VLDL) and adipocyte (lipid vesicle) they are made by GPAT
inside cells (lipid droplets, VLDL)
made by ACAT
in the plasma (HDL)
made by LCAT
where are hormones made?
adrenal gland
a lot of steroid hormones can be made with cholesterol as a precursor
how is vitamin D made?
by reaction with UV light on the skin, cholesterol can turn into vitamin D which helps for bone development
cholesterol is transformed, not degraded
what do statins do?
inhibit HMG-CoA reductase and decrease LDL
increase concentration of LDL-R and no LDL in blood
