Cholesterol and bile acids

What is the main function of cholesterol and what 3 things it is a precursor to?

• structural component of cellular membrane (fluidity)

• precursor for: vitamin D, sterol hormones, and bile salts

What organ plays a central role in cholesterol homeostasis?

the liver

What the fused four ring system (labeled A-D) called for steroids and cholesterol?

steriod nucleus

sterols are a subclass of steroids that always contain a ____ at carbon and a___ at carbon ____

hydroxyl group at carbon 3

aliphatic chain at least 8 carbons long at carbon 17

Cholesterol has a ___ bond at carbon ___

double bond at carbon 5

Where on the sterol can be esterified to produce sterol esters?

the hydroxyl group at carbon 3

substituents below the plane of the ring are in ___ orientation and are ___ lines

alpha orientation

dashed lines

substituents above the plane of the ring are in ___ orientation and are ___ lines

beta orientation

solid lines

What is indicated with a delta and a subscript? what does the subscript mean?

double bonds, the subscript is at what carbon the double bond in located

What are 4 examples of steroid hormones and what is their precursor?

progesterone, testosterone, estradiol, and cortisol

cholesterol can turn into these steroid hormones

what enzyme catalyzes the rate-limiting step of bile acid synthesis from cholesterol?

7alpha-hydroxylase

explain plant sterols and cholesterol

what is the bottom line?

plants do not have cholesterol, they have other types like stigmasterol, sitosterol, and sitostanol

these plant sterols are not absorbed efficiently by the human digestive system so they are taken back into the intestinal lumen and they bring some cholesterol with them

bottom line: plant sterols in the diet can decrease the absorption of cholesterol in the diet

Which drug class tries to reduce intestinal cholesterol absorption? What does it target to do this?

ezetimibe

targets Niemann-Pick C1-like protein (NPC1L1)

If we want to decrease cholesterol levels in the body, what are 3 things we could do?

1. decrease dietary cholesterol uptake

2. decrease cholesterol biosynthesis

3. increase the excretion of bile acids/salts

What enzyme catalyzes the rate-limiting step and is the key regulatory point in cholesterol biosynthesis?

HMG CoA reductase (produces one mevalonate)

this is irreversible 

What enzyme is responsible for the transfer of acyl groups from fatty acid CoA to store in the cell as cholesterol esters (esterified)?

acyl CoA cholesterol acyltransferase (ACAT)

What enzyme is responsible for converting cholesterol to cholesterol esters by the transfer of an acyl group form carbon 2 of lecithin?

lecithin cholesterol acyltransferase (LCAT)

goes with HDL

What regulates the transcription of HMG CoA reductase? How?

sterol regulatory element binding protein (SREBP)

when cholesterol levels are low, SREB binds to SRE on the HMG CoA reductase gene and turns on its transcription 

Explain what happens to HMG CoA reductase when cholesterol is abundant

HMG CoA reductase mRNA is targeted for degradation and HMG CoA reductase protein is targeted for degradation by the proteasome

What is the imbalance between cholesterol and phospholipids and bile salts? What does that mean?

cholelithiasis (you get stones in the gallbladder)

What is one way we can decrease the re-absorption of bile salts thus decreasing cholesterol levels?

cholestyramine

Enterohepatic circulation refers to the recycling of what?

bile salts can be reabsorbed in the GI tract for re-circulation back to the liver

Bile acids an be conjugated to ___ or ___.

conjugated bile salts have a ___ pKa

glycine or taurine

conjugated = lower pKa

What is a better detergent? unconjugated or conjugated bile salts?

conjugated

a higher percentage of the ___ bile salts are present in the ionized form in the intestine

conjugated (remember they have a lower pKa so they like to dissociate into their ions if that makes sense)

Cholic acid and chenodeoxycholic acid are the ___ bile salts

primary

Deoxycholic acid and lithocholic acid are the ___ bile salts

secondary bile salts

they are formed from the primary bile salts by bacterial enzymes in the intestine

secondary bile salts are ___ soluble than primary, so they are more likely to be ____

less soluble, more likely to be excreted 

____ and _____ increase the solubility of bile salts

hydroxylation and carboxylation

What effect does hydroxylation and carboxylation have on the bile salts?

increases their solubility

since dietary lipids (fat) have low solubility, what acts as the detergents to emulsify the dietary lipids?

bile salts

____ is the precursor to bile salts and they are synthesized in the ____

cholesterol; liver

insulin activates a ____ which has what effect on cholesterol synthesis?

phosphatase; increase cholesterol synthesis

glucagon activates a _____ which has what effect on cholesterol synthesis?

kinase; decrease cholesterol synthesis

Phosphorylation of HMG CoA reductase ___ (reduces or increases) the activity which ____ (increases or decreases) cholesterol biosynthesis

what type of enzyme does phosphorylation?

kinase → phosphorylation → reduces activity of HMG CoA reductase → reduces biosynthesis of cholesterol  

note: glucagon

Dephosphorylation of HMG CoA reductase ___ (reduces or increases) the activity which ____ (increases or decreases) cholesterol biosynthesis

what type of enzyme does dephosphorylation?

phosphatase → dephosphorylation → increases activity of HMG CoA reductase → increase biosynthesis of cholesterol 

note: insulin