Cholesterol Metabolism

Transcript by dr. JM Source : Osmosis

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Cholesterol is a lipid molecule that helps maintain a structure of cell membrane and is

a precursor to steroid hormones, bile acids and vitamin D as it turns out we make most

of cholesterol ourselves but some comes through the diet.

Cholesterol synthesis also called the mevalonate pathyway happens in the smooth

endoplasmic reticulum of the cell.

It starts with 2 acetyl co A molecules getting join together by the enzyme acetyl co A

acyl transferase. The results are four carbon molecule called acetoacetyl coA and a

coA free molecule.

Next the enzyme HMG CoA synthase combined acetoacetylCoA and acetyl co A to

form a six carbon molecule called HMG coA. So three acetyls and then a free coA

molecule. Then an enzyme called HMG-CoA reductase reduced HMG-CoA to

mevalonate by removing a CoA-SH and a water molecule. This step with HMG-CoA

reductase is the rate limiting step of cholesterol synthesis in other words the rate of

this reaction determine the overall rate of cholesterol synthesis. It’s like the slowest

step in the assembly line for a factory.

Now cholesterol synthesisis is regulated by a trio protein, SREBP, and two others

that just go by SCAP and INSIG1.

Let’s say that cholesterol levels drop because there’s less cholesterol coming into the

cell from the diet. In that situation Insig1 falls of off SREBP like pulling a pin from a
grenade. And then SREBP SCAP complex then get cleaves by celullar enzymes. The

cleaves SREBP floats into the nucleus and bind into the sterol regulatory element on

the DNA. When it binds it increases expression of the genes encoding HMG-CoA

reductase that leaves to more HMG-CoA reductase which speeds up endogenous

cholesterol synthesis.

Once HMG CoA reductase has made the 6 carbon mevalonate it then undergoes a

number of additional enzyme mediated transformation before becomes cholesterol.

First the enzyme mevalonate 5 kinase uses adenosine triphosphate or ATP to

phosphorylate mevalonate creating mevalonate-5-phosphate then phosphome valonate

kinase uses another ATP to phosphorylate mevalonate-5-phosphate making

mevalonate pyrophosphate finally mevalonate pyrophosphate decarboxylase removes

a carboxyl group from it. Forming a 5 carbon molecule called isopentenyl

pyrophosphate next geranyl transferase condenses three of these isopentenyl

pyrophosphate molecule to form a 15 carbon molecule called farnesyl pyrophosphate

then the enzyme squalene synthase condenses two molecules of farnesyl

pyrophosphate to form a 30 carbon molecule called squalene. It’s the last linear

precursor to cholesterol.

Next an enzyme called oxidosqualene cyclase converts linear squalene molecule into

a structure with rings, a process called cyclization the results are first sterol

intermediate called lanosterol from there, there are 19 steps of excessive modifications

that converts lanosterol first into 27 carbon called 7 dehydrocholesterol then finally

into 27 carbon cholesterol.

If 7 dehydrocholesterol gets hit by a single photon of light in just the right way, then

you get VitaminD3 which is important for calcium and phosphate metabolism.
The majority of cholesterol is made and used by the liver ending up as a bile acids.

There are two types of bile acids cholic acidsand chenodeoxycholic acids both get

conjugated by amino acids. Conjugation with taurine makes taurocholic acid and

taurochenodeoxycholic acid while conjugation with glycine makes glycocholic acid

and glycochenodeoxycholic acid.

These bile acids are stored in the gallbladder and released into the intestines after meal

to assist in fat digestion from the intestine some bile acids are eliminated through the

feces but most are reabsorbed by intestines and get into portal bloodstream back to

liver cells. This is called enterohepatic circulation.

Cholesterol insoluble in water so moving through the bloodstream is done through

lipoprotein which are part lipophilic or fat loving and part hydrophilic or water loving.

Aside from the liver, every cell can make cholesterol for itself one way cells used

cholesterol is as a part of a cell membrane, and the role of cholesterol is to fold.

at low temperature it squeezes inbetween phospholipid molecules and keeps them

from packing too tightly together to keep the membrane more fluid. In high

temperature cholesterol pulls together phospholipid molecules together decreasing the

space between them. So cholesterol makes the cell membrane fluid and durable no

matter the weather.

Finally cholesterol used by the adrenal glands and gonads to make steroid hormones.

Enzymes in the cortex of adrenal gland tweak cholesterol molecule to make

corticosteroids like cortisol and aldosterone which play a role in our fligh or fight

response in regulating our blood pressure respectively. The gonads have a different

sets of enzyme that metabolyze cholesterol a bit differently the testes mostly use

cholesterol to make testosterone while the ovaries mostly used cholesterol to sythesize

estradiol and progesterone.