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A behind the scenes look at cholesterol production
You need cholesterol………….
It is estimated that, you need around 1 g of cholesterol a day.
Despite cholesterol’s bad reputation, it’s a precursor for the synthesis of
- bile acids,
- steroid hormones and
- a critical component of cell membranes, where it modulates their function.
The body can make it, from scratch or it can, take advantage of the cholesterol that comes in, from the diet.
To make it, from scratch, is a mammoth undertaking.
It takes 30 steps, to go from acetyl Co A to a newly minted cholesterol molecule.
So, you guessed it ………. the average liver, is only too pleased to get it ready made, from dinner.
A low cholesterol diet
But, if the dinner is low on cholesterol.
And there is a need, inside the liver.
The liver, allocates the necessary resources, to produce, what is needed…. and the liver, needs a generous supply of cholesterol, because cholesterol is involved in lipoprotein vehicle construction.
NB. The liver is in the fat moving business !
The cholesterol production line
The enzyme, at the start of the cholesterol production line, is HMG co-reductase. He is not an especially charismatic enzyme, but he is a hard worker……… and he is a company man.
He takes orders well.
And will go the extra mile, and work overtime, if asked to, by the management.
These qualities, have led HMG, to a supervisory role, on the production line. His official designation is….. the rate limiting enzyme of cholesterol production.
It sounds quite grand, but he is very much a supervisor, not a manager.
He controls the speed at which production happens….
A chief in title only
But has very little control, over when production happens. This is controlled by the higher ups….
And, they can sometimes be, RATHER DEMANDING.
Even un-reasonable !
Officially, his contract states the cholesterol production, should happen, during the day shift.
The chief’s contract
HMG-co reductase’s contractual obligations, require him to show up for work, following a grocery run. In some people, this happens, SERIOUSLY early, in the others, he gets to lie in, until noon. Of course, usually in these people, the kitchen remains open, REALLY, REALLY late.
Whenever it happens, insulin let’s HMG co-reductase know, his services are needed.
HMG-co reductase, sets about turning, the groceries, into cholesterol, if and when, cholesterol is needed.
Staffing the cholesterol production line
Exactly how many HMG co-reductase enzymes, show up for work on any given day, is planned and co-ordinated, by a member of the HR team, commonly referred to as SREBP.
SREBP continually accesses the cellular sterol levels…..
When shortages, are detected, SHREP arranges for more cholesterol production lines, to come on line, by increasing production of all the workers, including HMG co-reductase. When supplies are adequate, a skeleton staff, is enough, to keep, going.
Knocking off work
The story plays out, every time a grocery delivery is made. And, since it is common for deliveries, to continue, late into the night, cholesterol production, often happens, late into the night.
But, when feeding is done for the day and the kitchen, has been closed, E3 ligase gp78, signs HMG co-reductase out.
When HMG co-reductase, has clocked out, he heads “home”.
The metaphorical HOME
Now, if you’re imagining, HMG co-reductase goes home, to the wife and kids, he doesn’t. Signing out, involves getting ubiquinated by E3 ligase gp 78 and then………… as a ubiquinated protein, he is vaporized, in the proteosome
I know, I know, it sounds harsh, but this is how life is, inside a cell and being vaporized in the proteasome, facilitates re-incarnation, as another protein, because the amino acids are continuously recycled.
With HMG co-reductase GONE, the cholesterol production line is idle, for a few hours………
Well, at least, this is how, it’s meant to work.
Timing cholesterol production
Feeding induces cholesterol production and fasting, represses cholesterol biosynthesis, because insulin comes and goes, with each feeding occasion.
But, in the metabolically broken………… insulin NEVER knocks off.
Insulin is around, morning, noon AND NIGHT.
No worries, gp78, the dude that signs HMG co-reductase out, will ensure the cholesterol production line, goes idle…
Welcome to the dark side
NOT so fast…..
Powerful DARK FORCES, keep insulin circulating.
And cholesterol production, NEVER CEASES.
Despite rumours of INSULIN RESITANCE, the cholesterol production line, is one pathway that is continuously INSULIN RESPONSIVE. One of the reasons, Gp78, gets instructions from one of the big bosses, mTOR, via a minion, known as USP20.
NOTE : For the record, scientists are working on a drug, that would take USP20, out of the picture, but this is years away.
mTOR keeps USP20, primed and phosphorylated, so….
HMG co-reductase is NOT signed out.
And cholesterol production continues – ALL DAY and ALL NIGHT !
The result……. levels of cholesterol, in the circulation, are higher than IDEAL.
Let’s go to war
Since “High” cholesterol IS ASSOCIATED with cardiovascular disease.
We should lower CHOLESTEROL, by any and all means, at our disposal.
The current go to approach, is to disable HMG co-reductase. This is what , the class of drugs, known as statins do……. they inhibit HMG co-reductase activity.
It works, production is turned down.
In some circumstances, this reprieve in production, can be most helpful, but, since cholesterol production is not a nice to have, but a necessity, this too, can have unwanted consequences.
NOTE : To maximize the inappropriate cholesterol production and minimize the impact on normal cholesterol production, timing when the statin is in the system, will help. Several clinical trials have demonstrated, taking statins at night, rather than in the morning, is as effective or more effective.
HMG co-reductase a victim of circumstance
The biology is clear, HMG co-reductase is the victim – the poor guy is subject to the whims of an out of control, insulin.
To create BETTER BODY CHEMISTRY, insulin must be reined in.
Getting this right, will cause cholesterol levels, to be lower.
So if you want to stop cholesterol, STOP insulin, a good place to start is to CANDY FLOSS. Download “The Willpower Report”, it’s free, to learn how.
The war on cholesterol, although laudable, is not going to “fix” atherosclerosis, because the blockage starts deep inside the blood vessel, the vasa vasorum is to blame
A cell lining a blood vessel suffers a catastrophic event AND IS NOT REPLACED, because you’re short of EPCs – cholesterol then fills the leaking pipe, and so it begins.
Substituting vegetable oils for saturated fat, definitely lowers your cholesterol levels. But does this protect your from heart disease ? In a word – NO.