Biochemistry Cholesterol Metabolism

Question 1

Which tissues synthesize cholesterol

Answer 1

essentially all nucleated cells - Liver accounts for 50% of synthesized cholesterol, steroid hormone producing cells are also very active

Question 2

where is cholesterol synthesized within the cell

Answer 2

cytosol and endoplasmic reticulum

Question 3

What are the carbon atoms of cholesterol derived from

Answer 3

acetyl-CoA

Question 4

What is the rate limiting step/major control point of cholesterol metabolism? What drugs inhibit this step?

Answer 4

HMG CoA-reductase - inhibited by statins

Question 5

Where is HMG-CoA reductase found

Answer 5

it is an endoplasmic reticulum embedded enzyme

Question 6

formation of isopentenyl diphosphate includes what steps

Answer 6

4 steps, sequential phosphorylation by 3 kinases (3ATP) and decarboxylation

Question 7

What reaction is synthesized by HMG-CoA reductase

Answer 7

HMG CoA is reduced to mevalonate

Question 8

What cofactors are required by HMG-CoA reductase

Answer 8

2 NADPH + 2H+

Question 9

describe the formation of a squalene

Answer 9

1.) 2 isoprenoid units are used to form geranyl diphosphate 2.) A thrid isoprenoid unit is added to form darnesyl diphosphate 3.) two farnesyl diphosphates are used to synthesize sqalene

Question 10

Name the positive regulators of HMG CoA reductase

Answer 10

Promote dephosphorylation of HMG CoA reductase : 1.) Insulin 2.) Thyroxine (thyroid hormone)

Question 11

Name the negative regulators of HMG CoA reductase

Answer 11

Promote phosphorylation of HMG CoA 1.) Glucagon 2.) Glucocorticosteroids 3.) Cholesterol

Question 12

Describe: Squalene to Lanosterol

Answer 12

1.) Squalene epoxidase (requires NADPH and O2) 2.) Lanosterol cyclase

Question 13

What is the first sterol produced in the pathway to cholesterol

Answer 13

Lanosterol

Question 14

Name the five steps between lanosterol and cholesterol

Answer 14

1.) Removal of methyl group at C14 2.) Removal of 2 methyl groups at C4 3.) Reduction of C24 double bond 4.) Moving the double bond from 8-9 to 5-6

Question 15

where does the conversion of lanosterol to cholesterol take place

Answer 15

in the endoplasmic reticulum

Question 16

what are the “Other products” produced in the cholesterol synthesis pathway

Answer 16

1) Prenylated proteins 2.) Dolichol 3.) Ubiquinone

Question 17

Prenylated proteins

Answer 17

membrane associated proteins (GTP-binding proteins) prenylated with farnesyl or geranylgeranyl residues. Function: Anchor protiens to the membrane

Question 18

Dolichol

Answer 18

formed from farnesyl diphosphate plus up to 16 more isopentyl residues. Dolichol is required for the synthesis of N-linked glycoproteins

Question 19

Ubiquinone

Answer 19

formed from farnysyl diphosphate plus 3-7 isopentenyl residues. Required for the electron transport chain

Question 20

Fates of cholesterol in the liver

Answer 20

1.) Formation of cholesteryl esters that get transported to other tissues 2.) Secreted into bile 3.) Synthesized into bile acids and bile salts

Question 21

what enzyme is involved in cholesteryl ester synthesis

Answer 21

ACAT (Acyl CoA-cholesterol acyltransferase

Question 22

Tissues use cholesteryl esters for what

Answer 22

1.) Steroid hormone synthesis 2.) Vitamin D synthesis

Question 23

What are the only ways we have to get rid of cholesterol

Answer 23

1.) Secrete it into bile 2.) Synthesize into bile acids and their salts

Question 24

What is the only way the body can open the steroid ring

Answer 24

Convert to vitamin D

Question 25

What is the committed step of bile acid synthesis

Answer 25

7a-hydroxylase

Question 26

What is the main organ for control of whole body cholesterol metabolism

Answer 26

Liver

Question 27

Major site of cholesterol synthesis

Answer 27

Liver

Question 28

Liver secretes cholesterol into the blood stream via

Answer 28

VLDL

Question 29

What are the three regulatory targets of the liver

Answer 29

1.) HMG-CoA reductase (cholesterol synthesis) 2.) LDL receptor 3.) 7a-Hydroxylase (bile acid synthesis)

Question 30

Transcriptional control of cholesterol synthesis

Answer 30

SREBP (sterol-regulatory element binding protein) binds to the SRE (sterol regulatory element) of HMG-CoA reductase to stimulate transcription of the gene. Elevated amounts of cholesterol will prevent SREBP binding - instead it interacts with SCAP (SREBP cleavage activating protein) which contains a sterol binding domain, as long as cholesterol is around the SREBP stays bound to SCAP within the ER. When cholesterol levels fall cholesterol leaves the SCAP binding site and the SREBP: SCAP complex then moves to the golgi where SREBP is released and allowed to travel to the nucleus to bind SRE

Question 31

Proteolysis of HMG- CoA reductase

Answer 31

when the sterol sites are occupied by cholesterol the enzyme is more susceptible to proteolysis

Question 32

Regulation of HMG CoA reductase through phosphorylation/dephosphorylation

Answer 32

HMG-CoA reductase is less active when phosphorylated

Question 33

what regulates the synthesis of LDL receptors

Answer 33

intracellular cholesterol content

Question 34

Transcriptional control of LDL receptors

Answer 34

under the same control as HMG-CoA reductase = SREBP binding to SRE of the LDL receptor gene. Elevated cholesterol will prevent the binding to the LDL receptor gene (same mechanism as HMG-CoA reductase)

Question 35

What promotes the destruction of LDL receptors

Answer 35

PCSK9

Question 36

What represses the syntheis of 7a-hydroxylase

Answer 36

increased bile acids in the liver - bile acid binds farnesyl X-receptor (FXR) and this complex supresses 7a-hydroxylase synthesis