Cholesterol Biosynthesis

Question 1

Cholesteryl ester

Answer 1

cholesterol + fatty acid (hydrophobic)

Question 2

LIver and cholesterol

Answer 2

Sources: chylomicron remnants; cholesterol syntesized in extrahepatic tissues (HDL); de novo syntiesis
How it leaves: free cholesterol in bile, VLDLs, Bile salts/acids

Question 3

Cholesterol

Answer 3

4 rings, 27 carbons, amphipathic (barely, enough to be in membrane)

Question 4

Requirements of cholesterol synthesis

Answer 4

Ac-CoA, NADPH, ATP

Question 5

Rate limiting step of cholestrol synthesis

Answer 5

HMG CoA reductase

Question 6

Thynthesis of HMG-CoA

Answer 6

Thiolase
2 Ac-CoA ———–>Acetoacetyl-CoA

                                HMG-CoA synthase Acetoacyl-CoA + Ac-CoA------------->HMG-CoA

Question 7

Thiolase

Answer 7

aka Ac-CoA acyltransferase

2 Ac-CoA–>acetoacetyl CoA + CoA

Question 8

HMG-CoA synthase

Answer 8

Acetoacy-CoA + Ac-CoA—->2-hydroxy-3-methylglutaryl-CoA (HMG CoA) + CoA

Question 9

HMG CoA reductase

Answer 9

HMG-CoA + 2 NADPH–>Mevalonate + 2 NADP+
(carbonyl–>alcohol)

Inhibited: Cholesterol, Glucagon (PKA phosphorylates), statins (competitive inhibition, over long term leads to upregulation due to low cholesterol levels), mevalonate (product inhibition), AMP kinase (high [AMP] stimulates)
Activated: Insulin

Cholesterol regulates: using product inhibition, modulating gene expression, promoting degredation

Question 10

2nd Part of cholesterold biosynthesis

Answer 10

mevalonate + 2 ATP –>–> 5-pyrophosphomevalonate + ATP –>IPP —>DPP
Decarboxylase isomerization

            Transferase
DPP + IPP-->GPP +PPi
              Transferase
GPP + IPP --> FPP
               Squalene synthase
2 FPP + NADPH------->Squalene

Squalene + NADPH + O2—->Lanosterol + H2O+NADP+ cyclization

Lanosterol–>–>–>Cholesterol

Also:
FPP and IPP–>dolichol or ubiquinone
FPP and GPP–>protein prenylation

Question 11

All intermediates in cholesterol synthsis

Answer 11

Ac-CoA (2C) –>Acetoacyl-CoA (4C) –>HMG-CoA (6C) –>Mevalonate (6C) –> Pyrophosphomevalonate (6C)f–>isopentylpyrophosphate (IPP, 5C) –> 3,3-dimethylallylphyrophosphate (DPP, 5C) –> geranylpyrophosphate (10C, GPP) –> Farnsylpyrophosphate (FPP, 15C) –> Squalene (30C) –> Lanosterol (30C) –> Cholesterol (27C)

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Question 12

SREBP

Answer 12

Sterol regulatory element binding protein:
released from ER in response to low [cholesterol]
binds to Sterol responsive element (SRE, enhancer) upregulates transcription of hmg coA reductase

Question 13

SCAP

Answer 13

SREBP cleavage-activating protein

inhibits SREBP and therefore hmg coa reductase

Question 14

LDL

Answer 14

in plasma: highest amount of cholesterol of any lipoprotein

taken up by endocytosis after binding LDL receptor in liver

Question 15

Long term effects of statins

Answer 15

increased transcription/translation of hmg-CoA reductase
Upregulation of LDL receptor
increase in uptake of LDL
recudtion in serum cholesterol

Question 16

ACAT

Answer 16

acyl-CoA:cholesterol acetyl transferase, upregulated by intracellular cholesterol

creates cholesteryl esters that are stored

Question 17

SLOS

Answer 17

Smith-Lemli-Opitz Syndrome

7-dehydrocholesterol reductase partial deficiency (needed for forming dbl bond in ring B)

microencephaly (IQ 20-40)

Characteristic dysmorphic faces
Microcephaly
Syndactyly (most commonly of the second and third toes)
Polydactyly
Growth retardation
Intellectual disability
Cleft palate
Hypospadias (males)

Question 18

Degredation of Cholesterol

Answer 18

Doesn’t happen in humans

Excreted as bile salts in feces or as cholestanol or coprostanol (modified by intestinal flora)

Question 19

7-alpha-hydroxylase

Answer 19

Rate limiting step in bile acid synthesis (adds OH to carbon 7)

Activated: cholesterol
Inhibited: cholic acid

Question 20

Bile salts

Answer 20

Cholic acid and chenodeoxycholic acid conjugated with glycine or taurine to form:
glyco… or tauro…

bacteria remove hydroxyl groups to form:
deoxycholic acid, and lithocholic acid

Question 21

Cholelithiasis

Answer 21

Bile salt deficiency-deficiency of letithin or bile saltes causes cholesterol to precipitate in gall bladder