Cholestrol and bile salt synth

What is cholestrol a precursor to? 

Steroid hormones and Bile salts

Where is cholestrol synthesized

In the cytosol and ER

What does the liver do in cholesterol metabolism?

Processes the lipoproteins, synthesized large quantities of cholestrerol for export and bile salts for digestion, excretes cholesterol and bile salts into the intestine

What kind of tissues need a lot of cholestrol

Tissues that produce and excrete steroid hormones

What is most dietary cholesterol in the form of?

Cholestrol esters

What are cholesterol esters hydrolyzed by? 

Pancreatic esterase

When are cholestrol esters hydrolyzed?

Prior to uptake of the cholesterol and FAs by enterocytes

What do enterocytes absorb?

Cholesterol that is released in the bile

What inhibits cholesterol absorption

soluble dietary fibers

What drug inhibits cholesterol absorption

Ezetimbe (Zetia)

What can eliminate excessive cholesterol and plant sterols?

ABCG5, ABCG8

What are ABCG5 and ABCG8 members of?

ATP-Binding-Cassette transporter family

What do deficiencies in ABC transporter family cause?

Elevated serum cholesterol and plant sterols

What is excess serum cholesterol and plant sterols called? 

Phytosterolemia

What do ABC transporters also play a key role in?

Drub metabolism (liver), and drug resistance in bacteria and cancer cells

What is a possible source of cholesterol?

Acetyl-CoA in all cells of the body

What organs have the most active cholesterol synthesis

Liver, intestine, adrenal cortex, and reproductive tissue

How many carbons of cholestrol come from Acetyl CoA? 

All 27

What does cholestrol require for reduction

NADPH

Where is the NADPH needed for cholestrol reduction come from?

PPP and malic enzyme

Synthesis of cholesterol occurs in the cytoplasm, and will thus require the
transport of acetyl-CoA across the mitochondrial membrane in the form of

Citrate

How many stages does cholesterol synthesis occur in?

4

Is a high or low concentration of acetyl CoA needed to drive the reaction towards acetoacetyl CoA?

High

What is removed from two acetyl CoA to form acetoacetyl CoA?

CoA-SH

What turns Acetoacetyl CoA into HMG CoA

HMG CoA synthase

This cytosolic isoform of HMG CoA synthase is important in the
synthesis of cholesterol. The mitochondrial HMG CoA synthase
is important in the synthesis of

ketone bodies

What turns acetoacetyl CoA into HMG-CoA

HMG CoA synthase

What is removed from the acetoacetyl CoA to form HMG CoA

CoA-SH

What turns HMG-CoA into mevalonate

HMG CoA reductase

What is put into HMG CoA reductase

2NADPH+2H

What comes out of HMG CoA reductase

2 NADP and CoA-S

What is the rate limiting and committed step of mevalnoate from acetyl-CoA 

HMG CoA reductase

What kind of medication inhibits HMG CoA reductase?

Statins

What regulates HMG CoA reductase transcription

Cellular cholestrol concentrations

What is an SRE

Sterol regulatory element

What is a SREBP

Sterol regulatory element binding protein

What is a SCAP

SREBP clevage activating protein

Step one in HMG CoA reductase transcription

Cholesterol binds to SCAP

What does cholesterol binding to SCAP cause?

Intracellular cholestrol drop

What happens when intracellular cholesterol drops?

Cholestrol is released from SCAP

What is Step 2 of HMG CoA reductase transcription

SCAP/SREBP complex moves to golgi

What happens when the SCAP/SREBP move to the Golgi?

Proteases cleave SREBP DNA binding domain

What proteases cleave SREBP DNA binding domain?

S1P and S2P

What is step 3 of HMG CoA reductase transcription

SREBP DNA-binding domain moves to the nuleus

What happens when SREBP moves to the nulcease?

Transcription of the genes is stimulated, including the HMG CoA reductase, following the SRE

What is proteolysis of HMG CoA reductase regulated by?

Cellular sterol concentrations

What is reductase activity for proteolysis regulated by?

AMP activated proteins, kinase, glucagon, sterols, and insulin

What do rising levels of cholesterol and bile salts in hepatocytes cause? 

Induces a change in oliogomerization state of HMG CoA reductase in the ER membrane

What does a change in oliogomerization state of HMG CoA cause?

Increase proteolysis

What does AMP stimulate

AMP activated protein kinase

What does more AMP mean?

Cholestrol synth is inhibited

What encourgaed proteolysis and degradation

Sterols

is phosphorylated HMG CoA active or inactive

Inactive

What triggers HMG CoA reductase phosphorylation?

AMP activated kinase, and glucahon and intercellular sterols

What is stage two of cholestrol synth

Mevalontate is converted into an activated isoprene

What is used in synthesis of coenxyme Q and dolichol phosphate, among other things

Isopentyl Pyrophosphate and dimethylallyl pyrophosphate

How much ATP does mevalonate to 5-pyrophoaphate mevalonate use? 

2 ATP

How much atp does 5-pyrophosphate mevalontae to 3-phospho-5pyrophosphate mevalonate use?

1

What happens in stage 3

6 Activated isoprenes are condensed to form the 30 carbon molecule squalene

Where was geranol fround

geraniums

Where was farnesol found

flowers of the farnese acacia tree

What are geranyl PP and farenysyl PP used in?

Prenylation of membrane associated proteins

Side effects of statins?

Deficiencies in protein prenylation

What do diemethylallyl pyrophosphate and delta² isopentenyl pyrophosphate combine to form?

Geranyl pyrophosphate

What is excreted when diemethylallyl pyrophosphate and delta² isopentenyl pyrophosphate combine? 

PPi

What does geranyl pyrophosphate form?

farnesyl pyrophosphate

What does farnesyl purophosphate to squalene form?

NADP and 2PPi

What is stage 4

cyclication of squalene

What happens to squalene in stage four? 

Oxidized and cylixed to form lanosterol

What happens to lanosterol

Undergoes several reactions to produce cholesterol

What does squalene monooxygenase use to reduce O2

NADPH

What does O2 get reduced to by squalene

H2O

Where is the other O from O2 added? 

C2 double bond

What does the C2 double bond formed by squalene produce?

reactive expoxide

What does the cylase do the squalene epoxide do?

Facilitates closing of the rings

How many steps are there between lanosterol and cholesterol

20

What is the 1st fate of cholesterol

Incorporated into hepatic membranes 

Second fat of cholestrol

Converted into cholestrol esters and put into lipoproteins

What lipoproteins do cholestrol typically enter

VLDL

What tissues take up cholestrol in the form of lipoproteins

Extrhepatic tissues that can’t make enough cholestrol on their own

3rd fate of cholestrol

Secreted into bile to be absorbed from the intestine

What is the 4th fate of cholestrol

Converted to bile salts

What fates are most common for cholestrol

Conversion to lipoproteins, and reabsorbed by intestine

What are minor fates of cholestrol

Conversion to bile salts and incorperated into hepatic membranes

What is the first step of bile salt synthesis

Conversion of cholestrol inro 7a hydroxycholestrol

What does the NADPH in the first step of bile salt contribute

Provides electrons to reduce one of the atoms to water

What happens to the O in bile salt synthesis that isn't turned into water

Added to the 7th position

What is ta hydroxylase inhibited by?

feedback inhibition by bile salts

What is 7a hydroxycholesterol converted to? 

chenodeoxycholic acid and cholic acid

The pKa values of these bile salts are close to 6; they will be about ______%
deprotonated in the intestinal lumen

99

What are cholic acid and chenodeoxycholic acid conjugated with?

Taurine or glycine

What happens after chlic acid and chenodeoxycholic acid are conjucated

pKa value decreased

What does a low pKa mean

More effective at emulsifying 

What must occur before taurine and glycein attach

Carboxyl group is activated with CoA

At what place on the bile salt do intestinal bacteria deconjugate and dehydroxylate

C7

What does deconjugation of intestinal bacteria do?

Dehydroxylate the bile salts

What does dehydroxylation at C7 produce? 

Secondary bile salts

What percent of bile salts are recycled?

95%

At which place are bile salts only reconjugated

Liver

Why are bile salts only reconjugated in the liver

So they can be recycled